TW202400603A - Compounds as inhibitors of axl - Google Patents

Abstract

Compounds of Formula I that inhibit AXL, and compositions containing the compound(s) and methods for synthesizing the compounds, are described herein. Also described are the use of such compounds and compositions for the treatment of a diverse array of diseases, disorders, and conditions, including cancer, that are mediated, at least in part, by AXL.

Description

Compounds that are AXL inhibitors

The following discussion is provided to help the reader understand the disclosure and is not an admission that it describes or constitutes prior art.

AXL is a receptor tyrosine kinase (RTK) belonging to the TAM family. AXL regulates important processes such as cell growth, migration, aggregation and apoptosis. AXL can be activated by multiple mechanisms, including ligand-dependent and ligand-independent mechanisms. Once activated, AXL participates in multiple signaling pathways, including the RAS-RAF-MEK-ERK pathway, which leads to cancer cell proliferation, and the PI3K/AKT pathway, which is responsible for several pro-survival proteins.

AXL has been shown to be overexpressed in a variety of malignancies. In the cancer setting, AXL overexpression is associated with poor patient survival and resistance mechanisms (targeted and non-targeted).

In view of research linking AXL inhibition to diseases such as cancer, this technology requires new AXL inhibitors. The present disclosure addresses this need and provides additional advantages over previous AXL inhibitors.

In one aspect, the present disclosure relates to compounds that inhibit AXL activity. These compounds are represented by formula (I): (I) Or a pharmaceutically acceptable salt thereof, wherein: X is CR ⁵ or N; G ¹ is N or CR ^G1 ; G ² is CR ^G2 or N; G ³ is CR ^G3 or N; G ⁴ is CR ^G4 or N; G ⁵ is CR ^G5 or N; R ^G1 is selected from the group consisting of: H, C _1-3 alkyl, halogen, C _1-3 haloalkyl and CN; each R ^G2 , R ^G3 , R ^G4 and R ^G5 are independently selected from the group consisting of: H, halo, CN, C _1-7 alkyl, C _3-7 cycloalkyl, C _1-3 haloalkyl, -OC _1-3 alkyl , -OC _1-3 haloalkyl, -NR ^a R ^b and 5 to 8-membered heterocycloalkyl with 1-3 heteroatom ring vertices selected from the group consisting of O, N and S, and wherein cycloalkyl and heterocycloalkyl are substituted with 0-3 groups independently selected from the following groups: halo, CN, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 hydroxyalkyl, - OC _1-4 alkyl and OH; A is a fused ring selected from the group consisting of: cycloheptane, cyclohexane, cyclopentane, azepane, 1,4-oxaazepane , 1,4-diazacycloheptane, oxepane, tetrahydropyran, piperidine, bicyclo[4.2.1]nonane, bicyclo[4.1.1]octane, spiro[4.6]eleven alkane, 1-azaspiro[4.6]undecane and cyclooctane, each of which is substituted by 1 to 4 ^R2 and further by 0 or 1 pendant oxygen group located on the carbon atom adjacent to the nitrogen atom (= O) substitution; R ¹ is selected from the group consisting of: phenyl and a 5- to 6-membered heteroaryl group having 1 to 3 heteroatom ring vertices selected from the group consisting of O, N and S, and each phenyl group And heteroaryl is substituted by one R ^1a and 0-3 R ³ ; R ^1a is selected from the group consisting of: phenyl and one with 1-3 heteroatom ring vertices selected from the group consisting of O, N and S 5 to 6 membered heteroaryl, wherein the N atom is optionally oxidized when present, and each phenyl and heteroaryl is substituted by 0-4 R ⁴ ; each R ² is independently selected from the group consisting of: C _1-7 alkyl, C _3-7 alkenyl, C 3-7 alkynyl, C _3-7 cycloalkyl, -Y ₁ -OC _1-7 alkyl, ^{-Y 1 -OC} _3-7 cycloalkyl , -NR ^a R ^b , -C(O)-C _1-7 alkyl, -C(O)-C _3-7 cycloalkyl, -S(O) ₂ -C _1-7 alkyl, -S (O) ₂ -C _3-7 cycloalkyl, -C(O)NR ^a R ^b , 5 to 8 membered heterocycloalkyl, -NR ^a -(5 to 8 membered heterocycloalkyl), -C( O)-(5 to 8 membered heterocycloalkyl), -X ¹ -5 to 8 membered heterocycloalkyl and -OX ¹ -(5 to 8 membered heterocycloalkyl), wherein the heterocycloalkyl has 1- 3 heteroatom ring vertices selected from the group consisting of O, N and S, and each cycloalkyl and heterocycloalkyl is substituted by 0-3 groups independently selected from the following groups: halo, CN, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 hydroxyalkyl, -OC _1-4 alkyl and OH; each R ³ is independently selected from the group consisting of: halogen, CN, C _{1 -7} alkyl, C _2-7 alkenyl, C _3-7 alkynyl, C _1-4 haloalkyl, C _1-4 hydroxyalkyl, C _1-4 halohydroxyalkyl, -OC _1-7 alkyl group, -OC _1-6 haloalkyl, -NR ^a R ^b , -C(O)-NR ^a R ^b , -S(O) ₂ -NR ^a R ^b , -S(O)(NH)-C _1-7 alkyl, -S(O) ₂ -C _1-7 alkyl and -S(O) ₂ -C _1-7 haloalkyl; each R ⁴ is independently selected from the group consisting of: C _{1- 7} alkyl, halo, C _1-7 haloalkyl, -OC _{1-7 alkyl, -OC 1-7 haloalkyl} , CN, -C _1-7 alkyl-CN, hydroxyl, C _{1- 7hydroxyalkyl} , -C(O)NR ^a R ^b , C _3-7 cycloalkyl, -NR ^a -C(O)-C _1-7 alkyl, -NR ^a -C(O)-C _{3 -7} cycloalkyl, -NR ^a R ^b , -OC _1-4 alkylene -OC _1-4 alkyl, one of the ring vertices having 1 to 3 heteroatoms selected from the group consisting of O, N and S - O-(5 to 8 membered heterocycloalkyl), -5 to 8 membered heterocycloalkyl having 1 to 3 heteroatom ring vertices selected from the group consisting of O, N and S, -S(O) ₂ -C _1-7 alkyl, -S(O) ₂ -C _3-7 cycloalkyl, -S(O) ₂ -NR ^a R ^b , -NR ^a -S(O) ₂ -C _1-7 alkyl and -NR ^a -S(O) ₂ -C _3-7 cycloalkyl, wherein each cycloalkyl and heterocycloalkyl is substituted by 0 to 2 groups independently selected from the group consisting of: C _{1 -4} alkyl, halo and hydroxyl; or, two R ⁴ groups on the same ring vertex combine to form a side oxygen group (=O); or two R ⁴ groups on adjacent ring vertices combine to form a 1 to a 5- to 6-membered heterocycloalkyl group with 2 heteroatom ring vertices selected from the group consisting of O, N and S, wherein the 5- to 6-membered heterocycloalkyl group has 0 to 2 independently selected from the group consisting of Group substitution: C _1-4 alkyl and halo; R ⁵ is selected from the group consisting of: H, C _1-4 alkyl and -NH ₂ ; each X ¹ is C _1-7 alkyl or C _3-7 cycloalkyl; each Y ¹ is a C _2-7 alkyl or C _3-7 cycloalkyl; each R ^a and R ^b are independently selected from the group consisting of: H, C _1-7 Alkyl, C _1-7 haloalkyl, C _1-4 alkoxy C _1-4 alkyl, C _3-7 cycloalkyl, wherein the cycloalkyl is optionally substituted by -OC _1-3 alkyl; Or R ^a and R ^b together with the nitrogen to which they are attached form a 4 to 8 membered heterocycloalkyl ring having 0 to 2 additional heteroatom ring vertices selected from the group consisting of O, N and S, wherein the heterocycloalkyl The base ring is substituted by 0-3 groups, each group is independently selected from halo, CN, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 hydroxyalkyl, -OC _{1- 4} Alkyl group and X ¹ -OC _1-3 Alkyl group and OH; or two groups on the vertex of the same ring combine to form a side oxygen group (=O).

In another aspect, the disclosure relates to pharmaceutical compositions comprising a compound of the disclosure or a pharmaceutically acceptable salt thereof.

In another aspect, the present disclosure relates to methods of inhibiting AXL in a subject, comprising administering to the subject an effective amount of a compound described herein.

In yet another aspect, the present disclosure provides methods for treating a disease, condition, or disorder in a subject that is mediated, at least in part, by AXL, comprising administering to the subject a therapeutically effective amount of a compound described herein, or its Pharmaceutically acceptable salt. Diseases, conditions and disorders mediated by AXL include, for example, cancer, viral infections, and fibrosis. Certain aspects of the disclosure further include administration of one or more additional therapeutic agents as described below.

Cross-references to related applications

This application claims priority rights under 35 U.S.C. § 119(e) to U.S. Provisional Application Serial No. 63/356,421 filed on June 28, 2022, the disclosure of which is incorporated herein by reference in its entirety.

Before the present disclosure is further described, it is to be understood that the present disclosure is not limited to the specific embodiments set forth herein, and it is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting. sexual.

Where a range of values is provided, unless the context clearly requires otherwise, each intermediate value between the upper and lower limits of that range (to one-tenth of the unit of the lower limit) and any other designation within that stated range Values or intermediate values are included in this disclosure. The upper and lower limits of such smaller ranges may independently be included in the smaller ranges and are also covered by this disclosure, subject to any specific exclusivity limitations to the extent specified. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in this disclosure. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

Unless otherwise defined, all technical terms, symbols and other scientific terms or nouns used herein are intended to have meanings commonly understood by those skilled in the technical field to which this disclosure belongs.

As used herein, the term "about" has an approximate ordinary meaning and is intended to provide literal support for the exact number preceding it as well as a number that is near or approximately the number preceding the term. Generally speaking, the term "about" refers to the usual error range for each value that is readily known to those skilled in the art. If the degree of approximation is not otherwise obvious from the context, "about" means within plus or minus 10% of the value provided, or rounded to the nearest significant figure, in all cases including the value provided. Where a range is provided, it includes the bounding values. definition

Unless otherwise stated, the following terms are intended to have the meanings set forth below. Other terms are defined elsewhere throughout the specification.

Unless otherwise stated, the term "alkyl" by itself or as part of another substituent means a saturated straight or branched chain hydrocarbon radical having the specified number of carbon atoms ( i.e., C ₁ - ₈ means one to eight carbons). Alkyl groups may include any number of carbons, such as C _1-2 , C _1-3 , C _1-4 , C _1-5 , C _1-6 , C _1-7 , C _1-8 , C _1-9 , C _1-10 , C _2-3 , C _2-4 , C _2-5 , C _2-6 , C _3-4 , C _3-5 , C _3-6 , C _4-5 , C _4-6 and C _5-6 . Examples of alkyl groups include methyl (Me), ethyl (Et), n-propyl, isopropyl, n-butyl, tertiary butyl, isobutyl, tertiary butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl and the like. In some embodiments, alkyl is C _1-4 alkyl (eg, methyl, ethyl, isopropyl, or tertiary butyl).

The term "hydroxyalkyl" refers to an alkyl group as defined herein having a specified number of carbon atoms (eg, C _1-6 or C _1-8 ) and substituted with one or two hydroxyl (OH) groups.

The term "alkylene" refers to a straight or branched saturated aliphatic group having the specified number of carbon atoms and attached to at least two other groups, that is, divalent hydrocarbon groups. The two moieties attached to the alkylene group may be attached to the same atom or to different atoms of the alkylene group. For example, a linear alkylene group may be a divalent group -(CH ₂ ) _n -, where n is 1, 2, 3, 4, 5 or 6. Representative alkylene groups include, but are not limited to, methylene, ethylene, propylene, isopropylene, butylene, isobutyl, secondary butylene, pentylene, and hexylene. In some embodiments, alkylene groups may be substituted or unsubstituted. When an alkylene-containing group is optionally substituted, it will be understood that the optional substitution may be on the alkylene moiety of that moiety. In some embodiments, the alkylene group is C _1-3 alkylene (eg, methylene, ethylene, propylene, or isopropylene).

The term "cycloalkyl" refers to a monocyclic, bicyclic or polycyclic non-aromatic hydrocarbon ring system having the specified number of ring atoms ( eg , C _3-6 cycloalkyl has 3 to 6 ring carbon atoms). A cycloalkyl group can be saturated or partially unsaturated, that is, a cycloalkyl group can be characterized by one or more points of unsaturation, provided that the points of unsaturation do not give rise to an aromatic system. Examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, cyclooctenyl, cyclooctadienyl, and Similar. "Cycloalkyl" also refers to bicyclic and polycyclic hydrocarbon rings, such as bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, etc. In some embodiments, a cycloalkyl group of the present disclosure is a monocyclic C _3-5 cycloalkyl moiety (eg, cyclopropyl, cyclobutyl, or cyclopentyl).

The term "heterocycloalkyl" refers to a non-aromatic monocyclic, bicyclic or polycyclic cycloalkyl ring, which in some embodiments has 3 to 14 members (e.g., 3 to 14 membered heterocycles), or 3 to 10 members (e.g., 3 to 10 membered heterocycle), or 3 to 8 members (e.g., 3 to 8 membered heterocycle), or 3 to 6 members (e.g., 3 to 6 membered heterocycle), or 5 to 6 members (e.g., 5- to 6-membered heterocycle) with one to five, one to four, one to three, one to two, or one selected from nitrogen (N), oxygen (O), and sulfur (S) of heteroatoms. In some embodiments, the nitrogen and sulfur atoms of the heterocycloalkyl group are optionally oxidized (e.g., N-oxide (N ⁺ -O ^- ), trisine (S=O) or trisine (S(=O) ₂ )), and the nitrogen atoms are optionally quaternary ammonized. Heterocycloalkyl is saturated or has one or more points of unsaturation (for example, one or more carbon-carbon double bonds, carbon-carbon parabens, carbon-nitrogen double bonds and/or nitrogen-nitrogen double bonds). Characteristics, provided that unsaturated points do not produce aromatic systems. The rings of bicyclic and polycyclic heterocycloalkyl groups may be fused, bridged or spirocyclic. Non-limiting examples of heterocycloalkyl groups include aziridine, ethylene oxide, thiirane, pyrrolidine, imidazolidine, pyrazolidine, dioxolane, phthalimide, piperidine, 1,4 -Dioxane, morpholine, thiomorpholine, thiomorpholine-S-oxide, thiomorpholine-S,S-oxide, piperazine, 3,4,5,6-tetrahydropyridazine , pyran, decahydroisoquinoline, 3-pyrrolidine, thiopyran, tetrahydrofuran, tetrahydropyran, tetrahydrothiophene, quinuclidine, 2,6-diazaspiro[3.3]heptane, 2-nitrogen Azaspiro[3.3]heptane, 1-oxaspiro[3.3]heptane, 6-azaspiro[3.4]octane, 3-oxa-6-azabicyclo[3.1.1]heptane, 2- Oxa-5-azabicyclo[2.2.1]heptane, 3-oxa-8-azabicyclo[3.2.1]octane and the like. When chemically permitted, the heterocycloalkyl group can be connected to the rest of the molecule via a ring carbon atom or a ring heteroatom. In some embodiments, the heterocycloalkyl group of the present disclosure has one or two selected from N and O. The heteroatom or the monocyclic 5- to 8-membered heterocycloalkyl moiety of the heteroatom group (for example, oxazolidine, piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydropyran, dioxane, 3-oxo Hetero-6-azabicyclo[3.1.1]heptane or 2-oxa-5-azabicyclo[2.2.1]heptane).

As used herein, a wavy line intersecting a single, double or parabond in any chemical structure depicted herein " ” represents the point of attachment of a single bond, double bond, or parabond to the rest of the molecule. Furthermore, a bond extending from a substituent to the center of a ring (eg, a phenyl ring) is intended to mean that the substituent is attached to the ring at any available ring vertex, that is, such that attachment of the substituent to the ring results in a chemically stable arrangement.

Unless otherwise stated, the term "halo" or "halogen" by itself or as part of another substituent means a fluorine, chlorine, bromine or iodine atom. Additionally, terms such as "haloalkyl" are intended to include both monohaloalkyl and polyhaloalkyl groups. For example, the term "C _{1 -4} haloalkyl" is intended to include trifluoromethyl, difluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.

The term "aryl" refers to one ring or two or three rings fused together and in some embodiments has six to fourteen carbon atoms (i.e., C _6-14 aryl), or six to fourteen carbon atoms. Aromatic ring systems of ten carbon atoms (ie, C _6-10 aryl) or six carbon atoms (ie, C ₆ aryl). Non-limiting examples of aryl groups include phenyl, naphthyl, and anthracenyl. In some embodiments, aryl is phenyl.

The term "heteroaryl" refers to a monocyclic or fused bicyclic aromatic group (or ring), which in some embodiments has 5 to 14 members (i.e., ring vertices) (i.e., 5 to 14 members heteroaryl), or 5 to 10 members (i.e., 5 to 10 membered heteroaryl), or 5 to 6 members (i.e., 5 to 6 membered heteroaryl), and containing one to five, one to Four, one to three, one to two or one heteroatom selected from nitrogen (N), oxygen (O) and sulfur (S). In some embodiments, the nitrogen and sulfur atoms are optionally oxidized (e.g., N-oxide (N ⁺ -O ^- ), sulfur (S=O), or sulfur (S(=O) ₂ )), and the nitrogen The atoms are optionally quaternary ammonized. When chemically permitted, a heteroaryl group may be attached to the remainder of the molecule via a carbon atom or a heteroatom of the heteroaryl group. Non-limiting examples of heteroaryl include pyridinyl, pyridazinyl, pyrazinyl, pyrimidinyl, triazinyl, quinolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, benzene Triazinyl, purinyl, benzimidazolyl, benzopyrazolyl, benzotriazolyl, benzisoxazolyl, isobenzofuranyl, isoindolyl, indolizinyl, benzotriazyl Azinyl, thienopyridyl, thienopyrimidinyl, pyrazopyrimidinyl, imidazopyridine, benzothiazolyl, benzofuryl, benzothienyl, indolyl, quinolyl, isoquinolyl , isothiazolyl, pyrazolyl, indazolyl, pteridinyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiadiazolyl, thiolyl, thiazolyl, furan base, thienyl and the like. When a heteroaryl group is substituted, the substituent is attached to the heteroaryl group via a ring carbon atom or a ring heteroatom, where chemically permitted. In some embodiments, the heteroaryl systems of the disclosure are monocyclic 5- to 6-membered heteroaryl moieties containing 1-3 heteroatoms independently selected from N, O, and S, and wherein N atoms are present when Optionally oxidized (e.g., pyridyl, pyridyl N-oxide, pyrimidinyl, pyridazinyl, pyrazinyl, triazolyl, imidazolyl, pyrazolyl, oxazolyl, oxadiazolyl or thiazolyl ).

The compounds of the present disclosure may exist in their neutral form, or as a pharmaceutically acceptable salt, isomer, polymorph or solvate thereof, and may exist in crystalline form, amorphous form, or mixtures thereof exist.

The term "pharmaceutically acceptable salts" is intended to include salts of the active compounds prepared with relatively nontoxic acids or bases depending on the particular substituents found on the compounds described herein. When compounds of the present disclosure contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either pure or in a suitably inert form. in solvent. Examples of salts derived from pharmaceutically acceptable inorganic bases include aluminum, ammonium, calcium, copper, iron, ferrous iron, lithium, magnesium, manganese, manganese, potassium, sodium, zinc and the like. Salts derived from pharmaceutically acceptable organic bases include salts of primary, secondary and tertiary amines, including substituted amines, cyclic amines, naturally occurring amines and the like, such as arginine, betaine , caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylamine Phenoline, N-ethylpiperidine, glucosamine, glucosamine, histidine, herapamine, isopropylamine, lysine, methylglucosamine, morpholine, piperazine, piperidine, polyamine resin, general Lucaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like. When compounds of the present disclosure contain relatively basic functional groups, acid addition salts may be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, which may be pure or in a suitable in inert solvents. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogen carbonic acid, phosphoric acid, monohydrogen phosphoric acid, dihydrogen phosphoric acid, sulfuric acid, monohydrogen sulfuric acid, and hydrogen iodide. Salts of acid or phosphorous acid and the like, and derived from relatively non-toxic organic acids such as acetic acid, propionic acid, isobutyric acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, bitter almond Salts of acids, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids such as glucuronic acid or galacturonic acid and the like (see, e.g., Berge, SM et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science, 1977 , 66 , 1-19). Certain compounds of the present disclosure contain basic and acidic functional groups that allow the compounds to be converted into base or acid addition salts.

The neutral form of a compound can be regenerated by contacting the salt with a base or acid and isolating the parent compound in a conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but for the purposes of this disclosure, such salts are equivalent to the parent form of the compound.

This disclosure also encompasses isomers (eg, stereoisomers and atropisomers) of the compounds described herein. For example, certain compounds of the present disclosure have asymmetric carbon atoms (chiral centers) or hindered rotation around a single bond; their racemates, diastereomers, enantiomers and atropisomers ( For example, R _a , _Sa , P and M isomers) are intended to be included within the scope of this disclosure. Stereoisomeric forms may be defined as ( R ) or ( S ) based on absolute stereochemistry, and/or depicted using dashes and/or wedges. When stereochemistry is described (e.g., use dashes and/or wedge ) is shown in a chemical structure, or when a stereochemical assignment (e.g., using the ( R ) and ( S ) symbols) is given a chemical name, it means that the depicted isomer is present and is substantially free of one or more other isomers. structures (e.g., when present, enantiomers and diastereomers). "Substantially free" of other isomers means that the ratio of the specified isomer to other isomers is at least 70/30, more preferably 80/20, 90/10 or 95/5 or higher. In some embodiments, the specified isomer will be present in an amount of at least 99%. Drawn as a solid line ( ) to a chemical bond with an asymmetric carbon means including all possible stereoisomers on that carbon atom (for example, enantiomers, diastereomers, racemic mixtures, etc.). In such cases, the compounds may exist as racemic mixtures, scalemic mixtures or mixtures of diastereomers.

Compounds of the present disclosure may also contain unnatural proportions of atomic isotopes at one or more of the atoms that make up such compounds. The unnatural ratio of an isotope can be defined as the amount found in nature to an amount consisting of 100% of the related atoms. For example, the compounds may incorporate radioactive isotopes, such as tritium ( ³ H), iodine-125 ( ¹²⁵ I), or carbon-14 ( ¹⁴ C), or non-radioactive isotopes, such as deuterium ( ² H) or carbon-13 ( ¹³ C) . Such isotopic changes may provide additional utility to those described elsewhere herein. For example, isotopic variants of the disclosed compounds may find additional utility, including but not limited to, as diagnostic and/or imaging reagents, or as cytotoxic/radiotoxic therapeutics. In addition, isotopic variants of the disclosed compounds may have altered pharmacokinetic and pharmacodynamic characteristics, which may help enhance safety, tolerability, or efficacy during treatment. All isotopic variations of the compounds disclosed herein, whether radioactive or not, are intended to be included within the scope of this disclosure. In some embodiments, compounds according to the present disclosure are characterized by one or more deuterium atoms.

The terms "patient" or "individual" are used interchangeably to refer to humans or non-human animals (eg, mammals).

The terms "treat, treating, treatment" and the like mean to temporarily or permanently eliminate, reduce, suppress, alleviate, ameliorate or prevent the worsening of the disease, condition or disorder to which the term applies, or at least one of the symptoms associated therewith. course of action. Treatment includes alleviating symptoms, reducing disease severity, inhibiting (e.g., preventing the development or further development of a disease, condition, or disorder or clinical symptoms associated therewith) active disease, delaying or slowing disease progression, improving quality of life, and/or associated with A treatment that prolongs an individual's survival compared to the expected survival rate or compared to the published standard of care for a specific disease.

As used herein, the term "need for treatment" refers to the determination by a physician or similar professional that an individual needs or will benefit from treatment. This judgment is based on a variety of factors within the physician's area of expertise, which may include a positive diagnosis of a disease, condition, or disorder.

The terms "prevent, preventing, prevention, prophylaxis" and the like mean to initiate in some way (e.g., before the onset of a disease, disorder, disorder or symptoms thereof) to prevent, contain, suppress or reduce, temporarily or permanently A course of action that puts an individual at risk of developing or delaying the onset of a disease, disorder, disorder, or the like (e.g., as determined by the absence of clinical symptoms), typically in the case of an individual who is susceptible to a particular disease, disorder, or disorder. In some cases, these terms also refer to slowing the progression of a disease, condition or disorder or inhibiting its progression to a harmful or undesirable state. Prevention also refers to a course of action initiated in an individual to prevent the recurrence of a disease, disorder, disorder, or symptoms after the individual has been treated for the disease, disorder, disorder, or symptoms associated therewith.

As used herein, the term "need for prevention" refers to the determination by a physician or other caregiver that an individual needs or will benefit from preventive care. This judgment is based on various factors within the physician's or caregiver's area of expertise.

"Substantially pure" means that the component (eg, a compound according to the present disclosure) constitutes greater than about 50% of the total content of the composition, and typically constitutes greater than about 60% of the total content. More generally, "substantially pure" refers to a composition wherein at least 75%, at least 85%, at least 90% or more of the total composition is the component of interest. In some cases, the component of interest will comprise greater than about 90% or greater than about 95% of the total composition.

Selective compounds may be particularly useful in treating certain conditions or may reduce the likelihood of undesirable side effects. In some embodiments, compounds of the present disclosure are selective relative to other tyrosine kinases. Specific examples include TYRO3 and MER. Selectivity can be determined, for example, by comparing the inhibition of AXL by a compound described herein with the inhibition of another protein by a compound described herein. In one embodiment, selectively inhibiting AXL is at least 1000-fold greater, or 500-fold greater, or 100-fold greater, or 75-fold greater, or 50-fold greater, or greater than inhibiting another kinase (e.g., TYRO3 and/or MER). 40 times bigger, or 30 times bigger, or 25 times bigger, or 20 times bigger.

Compounds provided herein may have favorable pharmacokinetic characteristics, including, for example, inhibition of CYP, bioavailability, and/or inhibition of human Ether-a-go-go related gene (hERG) potassium channels. Compounds disclosed in this disclosure

In some aspects, provided herein are compounds represented by Formula (I) (I) Or a pharmaceutically acceptable salt thereof, wherein: X is CR ⁵ or N; G ¹ is N or CR ^G1 ; G ² is CR ^G2 or N; G ³ is CR ^G3 or N; G ⁴ is CR ^G4 or N; G ⁵ is CR ^G5 or N; R ^G1 is selected from the group consisting of: H, C _1-3 alkyl, halogen, C _1-3 haloalkyl and CN; each R ^G2 , R ^G3 , R ^G4 and R ^G5 are independently selected from the group consisting of: H, halo, CN, C _1-7 alkyl, C _3-7 cycloalkyl, C _1-3 haloalkyl, -OC _1-3 alkyl , -OC _1-3 haloalkyl, -NR ^a R ^b and 5 to 8-membered heterocycloalkyl with 1-3 heteroatom ring vertices selected from the group consisting of O, N and S, and wherein cycloalkyl and heterocycloalkyl are substituted with 0-3 groups independently selected from the following groups: halo, CN, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 hydroxyalkyl, - OC _1-4 alkyl and OH; A is a fused ring selected from the group consisting of: cycloheptane, cyclohexane, cyclopentane, azepane, 1,4-oxaazepane , 1,4-diazacycloheptane, oxepane, tetrahydropyran, piperidine, bicyclo[4.2.1]nonane, bicyclo[4.1.1]octane, spiro[4.6]eleven alkane, 1-azaspiro[4.6]undecane and cyclooctane, each of which is substituted by 1 to 4 ^R2 and further by 0 or 1 pendant oxygen group located on the carbon atom adjacent to the nitrogen atom (= O) substitution; R ¹ is selected from the group consisting of: phenyl and a 5- to 6-membered heteroaryl group having 1 to 3 heteroatom ring vertices selected from the group consisting of O, N and S, and each phenyl group And heteroaryl is substituted by one R ^1a and 0-3 R ³ ; R ^1a is selected from the group consisting of: phenyl and one with 1-3 heteroatom ring vertices selected from the group consisting of O, N and S 5 to 6 membered heteroaryl, in which the N atom is optionally oxidized when present, and each phenyl and heteroaryl is substituted by 0 to 4 R ⁴ ; each R ² is independently selected from the group consisting of: C _1-7 alkyl, C _3-7 alkenyl, C 3-7 alkynyl, C _3-7 cycloalkyl, -Y ₁ -OC _1-7 alkyl, ^{-Y 1 -OC} _3-7 cycloalkyl , -NR ^a R ^b , -C(O)-C _1-7 alkyl, -C(O)-C _3-7 cycloalkyl, -S(O) ₂ -C _1-7 alkyl, -S (O) ₂ -C _3-7 cycloalkyl, -C(O)NR ^a R ^b , 5 to 8 membered heterocycloalkyl, -NR ^a -(5 to 8 membered heterocycloalkyl), -C( O)-(5 to 8 membered heterocycloalkyl), -X ¹ -5 to 8 membered heterocycloalkyl and -OX ¹ -(5 to 8 membered heterocycloalkyl), wherein the heterocycloalkyl has 1- 3 heteroatom ring vertices selected from the group consisting of O, N and S, and each cycloalkyl and heterocycloalkyl is substituted by 0-3 groups independently selected from the following groups: halo, CN, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 hydroxyalkyl, -OC _1-4 alkyl and OH; each R ³ is independently selected from the group consisting of: halogen, CN, C _{1 -7} alkyl, C _2-7 alkenyl, C _3-7 alkynyl, C _1-4 haloalkyl, C _1-4 hydroxyalkyl, C _1-4 halohydroxyalkyl, -OC _1-7 alkyl group, -OC _1-6 haloalkyl, -NR ^a R ^b , -C(O)-NR ^a R ^b , -S(O) ₂ -NR ^a R ^b , -S(O)(NH)-C _1-7 alkyl, -S(O) ₂ -C _1-7 alkyl and -S(O) ₂ -C _1-7 haloalkyl; each R ⁴ is independently selected from the group consisting of: C _{1- 7} alkyl, halo, C _1-7 haloalkyl, -OC _{1-7 alkyl, -OC 1-7 haloalkyl} , CN, -C _1-7 alkyl-CN, hydroxyl, C _{1- 7hydroxyalkyl} , -C(O)NR ^a R ^b , C _3-7 cycloalkyl, -NR ^a -C(O)-C _1-7 alkyl, -NR ^a -C(O)-C _{3 -7} cycloalkyl, -NR ^a R ^b , -OC _1-4 alkylene -OC _1-4 alkyl, one of the ring vertices having 1 to 3 heteroatoms selected from the group consisting of O, N and S - O-(5 to 8 membered heterocycloalkyl), -5 to 8 membered heterocycloalkyl having 1 to 3 heteroatom ring vertices selected from the group consisting of O, N and S, -S(O) ₂ -C _1-7 alkyl, -S(O) ₂ -C _3-7 cycloalkyl, -S(O) ₂ -NR ^a R ^b , -NR ^a -S(O) ₂ -C _1-7 alkyl and -NR ^a -S(O) ₂ -C _3-7 cycloalkyl, wherein each cycloalkyl and heterocycloalkyl is substituted by 0 to 2 groups independently selected from the group consisting of: C _{1 -4} alkyl, halo and hydroxyl; or, two R ⁴ groups on the same ring vertex combine to form a side oxygen group (=O); or two R ⁴ groups on adjacent ring vertices combine to form a 1 to a 5- to 6-membered heterocycloalkyl group with 2 heteroatom ring vertices selected from the group consisting of O, N and S, wherein the 5- to 6-membered heterocycloalkyl group has 0 to 2 independently selected from the group consisting of Group substitution: C _1-4 alkyl and halo; R ⁵ is selected from the group consisting of: H, C _1-4 alkyl and -NH ₂ ; each X ¹ is C _1-7 alkyl or C _3-7 cycloalkyl; each Y ¹ is a C _2-7 alkyl or C _3-7 cycloalkyl; each R ^a and R ^b are independently selected from the group consisting of: H, C _1-7 Alkyl, C _1-7 haloalkyl, C _1-4 alkoxy C _1-4 alkyl and C _3-7 cycloalkyl, wherein the cycloalkyl is optionally substituted by -OC _1-3 alkyl; Or R ^a and R ^b together with the nitrogen to which they are attached form a 4 to 8 membered heterocycloalkyl ring having 0 to 2 additional heteroatom ring vertices selected from the group consisting of O, N and S, wherein the heterocycloalkyl The base ring is substituted by 0-3 groups, each group is independently selected from halo, CN, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 hydroxyalkyl, -OC _{1- 4} Alkyl group and X ¹ -OC _1-3 Alkyl group and OH; or two groups on the vertex of the same ring combine to form a side oxygen group (=O).

In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate or solvate thereof, is a compound, wherein ^G1 is N or CR ^G1 , wherein R ^G1 is H. In some embodiments, a compound of formula (I), or a pharmaceutically acceptable salt, hydrate or solvate thereof, is a compound, wherein G ¹ is N. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate or solvate thereof, is a compound, wherein ^G1 is CR ^G1 , and wherein ^RG1 is H.

In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate or solvate thereof, is a compound, wherein ^G2 is CR ^G2 , and wherein ^RG2 is H or F. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate or solvate thereof, is a compound, wherein ^G2 is CR ^G2 , and wherein ^RG2 is H. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate or solvate thereof, is a compound, wherein ^G2 is N.

In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate or solvate thereof, is a compound, wherein ^G3 is N or CR ^G3 , and ^RG3 is H or _CH3 .

In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate or solvate thereof, is a compound, wherein ^G4 is N or CR ^G4 , wherein R ^G4 is H.

In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate or solvate thereof, is a compound, wherein ^G5 is N or CR ^G5 , wherein ^RG5 is H.

In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate or solvate thereof, is a compound, wherein ^G1 is N, and ^G2 is CR ^G2 , wherein ^RG2 is H.

In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate or solvate thereof, is a compound, wherein ^G3 is CR ^G3 , and wherein ^RG3 is H.

In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate or solvate thereof, is a compound, wherein ^G4 is CR ^G4 , and wherein ^RG4 is H.

In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate or solvate thereof, is a compound, wherein ^G5 is CR ^G5 , and wherein ^RG5 is H.

In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate or solvate thereof, is a compound, wherein X is N or ^CR5 , and wherein ^R5 is H. In some embodiments, a compound of formula (I), or a pharmaceutically acceptable salt, hydrate or solvate thereof, is a compound, wherein X is ^CR5 , and wherein ^R5 is H.

Regarding A, it should be understood from the formula shown above that A is fused with the aromatic ring including G ³ , G ⁴ and G ⁵ , and the presence of A will not destroy the aromatic ring including G ³ , G ⁴ and G ⁵ of aromaticity. Specifically, the ring vertex that fuses the two rings together is an sp ² hybridized carbon atom. Therefore, each of these ring vertices has a p orbital participating in the conjugated pi system of the aromatic ring. Therefore, from the formula shown above it will be understood that part A has a point of unsaturation at the point of fusion with the rest of the molecule. For example, cyclopentane at A refers to cyclopentene in which the double bond is between two carbon atoms fused to the remainder of the compound, as further described and detailed throughout.

In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate or solvate thereof, is a compound, wherein A has a formula selected from the group consisting of: , and Each of them is substituted by 1 to 4 ^R2 .

In some embodiments, a compound of formula (I), or a pharmaceutically acceptable salt, hydrate or solvate thereof, is a compound, wherein A has a formula selected from the group consisting of: , and , each of which is substituted by 1 to 4 R ² .

In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof is a compound, wherein A has the formula , which is substituted by 1 to 4 R ² .

In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof is a compound, wherein A has the formula , where A is substituted by 1 to 4 R ² .

In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt, hydrate or solvate thereof, is a compound wherein A is substituted with at least one ^R2 selected from: -C _2-7 extension Alkyl-OC _1-4 alkyl and C _3-7 cycloalkyl. In some embodiments, a compound of formula (I), or a pharmaceutically acceptable salt, hydrate or solvate thereof, is a compound wherein A is substituted with at least one ^R selected from: and .

In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, hydrate or solvate thereof, is a compound, wherein A has the formula: or .

In some embodiments, a compound of formula (I), or a pharmaceutically acceptable salt, hydrate or solvate thereof, is a compound, wherein A has the formula: .

In some embodiments, a compound of formula (I), or a pharmaceutically acceptable salt, hydrate or solvate thereof, is a compound, wherein A has the formula: .

In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof is a compound, wherein ^each R is independently selected from the group consisting of: C _1-7 alkyl , C _3-7 alkenyl, C _3-7 alkynyl, C _3-7 cycloalkyl, -Y ¹ -OC _1-7 alkyl, -Y ¹ -OC _3-7 cycloalkyl, -NR ^a R ^b , -C(O)-C _1-7 alkyl, -C(O)-C _3-7 cycloalkyl, -S(O) ₂ -C _1-7 alkyl, -S(O) ₂ - C _3-7 cycloalkyl, -C(O)NR ^a R ^b , 5 to 8 membered heterocycloalkyl, -NR ^a -(5 to 8 membered heterocycloalkyl), -C(O)-(5 to 8-membered heterocycloalkyl), -X ¹ -5 to 8-membered heterocycloalkyl and -OX ¹ -(5 to 8-membered heterocycloalkyl), wherein the 5- to 8-membered heterocycloalkyl, -NR ^a -(5 to 8 membered heterocycloalkyl), -C(O)-(5 to 8 membered heterocycloalkyl), -X ¹ -5 to 8 membered heterocycloalkyl and -OX ¹ -(5 to 8 membered heterocycloalkyl) 8-membered heterocycloalkyl) has 1-3 heteroatom ring vertices selected from the group consisting of O, N and S, and wherein the C _3-7 cycloalkyl, -Y ¹ -OC _3-7 cycloalkyl , -C(O)-C _3-7 cycloalkyl, -S(O) ₂ -C _3-7 cycloalkyl, 5 to 8 membered heterocycloalkyl, -NR ^a -(5 to 8 membered heterocycle Alkyl), -C(O)-(5 to 8-membered heterocycloalkyl), -X ¹ -5 to 8-membered heterocycloalkyl and -OX ¹ -(5 to 8-membered heterocycloalkyl) are each 0-3 substituted groups independently selected from the following groups: halo, CN, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 hydroxyalkyl, -OC _1-4 alkyl and Oh . In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate or solvate thereof, is a compound wherein one R ² is -NR ^a R ^b .

In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt, hydrate or solvate thereof, is a compound in which one ^R is selected from the group consisting of: , , , , , and .

In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, hydrate or solvate thereof, is a compound wherein one ^R is .

In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof is a compound, wherein ^R1 is selected from the group consisting of: phenyl, pyridyl, pyridazinyl , pyrimidinyl, pyrazinyl, oxadiazolyl and pyrazolyl, wherein R ¹ is substituted by one R ^1a and 0-2 R ³ . In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof is a compound, wherein ^R1 is selected from the group consisting of: phenyl, pyridyl, pyridazinyl and pyrazolyl, wherein R ¹ is substituted with one R ^1a and 0-2 R ³ . In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof is a compound, wherein ^R is selected from the group consisting of: pyrimidinyl, pyrazinyl and oxadienyl Azolyl, wherein R ¹ is substituted by one R ^1a and 0-2 R ³ . In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, hydrate or solvate thereof, is a compound, wherein R ¹ is phenyl or pyridyl, wherein R ¹ is separated by one R ^1a and 0 -2 ^R3 replaced. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof is a compound, wherein R ¹ is pyridyl substituted with one R ^1a and 0-2 R ³ . In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof is a compound, wherein R ¹ is phenyl substituted with one R ^1a and 0-2 R ³ .

In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof is a compound, wherein ^R is selected from the group consisting of: , , , , , , , and , where the subscript p is 0 or 1.

In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof is a compound, wherein ^R is selected from the group consisting of: , , , , , , , , and , where the subscript p is 0 or 1.

In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof is a compound, wherein ^R is selected from the group consisting of: , , , ,and , where the subscript p is 0 or 1.

In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof is a compound, wherein ^R is selected from the group consisting of: , , and The subscript p is 0 or 1.

In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof is a compound, wherein ^R is selected from the group consisting of: , , , , , , . and , where the subscript p is 0 or 1.

In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, hydrate or solvate thereof, is a compound, wherein R ¹ is or The subscript p is 0 or 1.

In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, hydrate or solvate thereof, is a compound, wherein R ¹ is The subscript p is 0 or 1.

In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, hydrate or solvate thereof, is a compound, wherein R ¹ is The subscript p is 0 or 1.

In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate or solvate thereof, is a compound wherein ^R1 is substituted with 0 ^R3 groups. In some embodiments, a compound of formula (I), or a pharmaceutically acceptable salt, hydrate or solvate thereof, is a compound wherein R ¹ is substituted with 1 R ³ group.

In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof is a compound, wherein each R ³ when present is independently selected from the group consisting of: halogen, CN , C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 hydroxyalkyl, C _1-4 halohydroxyalkyl, -OC _1-4 alkyl, -OC _1-4 haloalkyl, -NR ^a R ^b , -C(O)-NR ^a R ^b , -S(O) ₂ -NR ^a R ^b , -S(O)(NH)-C _1-4 alkyl, -S(O) ₂ -C _1-4 alkyl and -S(O) ₂ -C _1-4 haloalkyl.

In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt, hydrate or solvate thereof, is a compound wherein each R ³ when present is independently selected from the group consisting of: halogen, C _1-4 alkyl and -OC _1-4 alkyl.

In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof is a compound, wherein each R ³ when present is independently selected from the group consisting of: chlorine, fluorine , methyl and methoxy.

In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt, hydrate or solvate thereof, is a compound wherein each R ³ when present is independently selected from the group consisting of: fluorine, methane and methoxyl groups.

In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof is a compound, wherein R ^1a is selected from the group consisting of: pyrazolyl, imidazolyl, triazole base, thiazolyl, oxazolyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyridyl N-oxide and phenyl, wherein R ^1a is substituted by 0 to 3 R ⁴ . In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof is a compound, wherein R ^1a is selected from the group consisting of: pyrazolyl, imidazolyl, triazole base, thiazolyl, oxazolyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl and phenyl, wherein R ^1a is substituted by 0-3 R ⁴ .

In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof is a compound, wherein R ^1a is selected from the group consisting of: , , , , , , , , , , , , , , , , , and The subscript q is 0, 1 or 2.

In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof is a compound, wherein R ^1a is selected from the group consisting of: , , , , , , , , , and , where the subscript q is 0, 1 or 2.

In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof is a compound, wherein R ^1a is selected from the group consisting of: , , , , , , , and , where the subscript q is 0, 1 or 2.

In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof is a compound, wherein R ^1a is selected from the group consisting of: and , where the subscript q is 0, 1 or 2.

In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof is a compound, wherein R ^1a is selected from the group consisting of: , , , , , , and , where the subscript q is 0, 1 or 2.

In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof is a compound, wherein R ^1a is selected from the group consisting of: , , , , , , and , where the subscript q is 0, 1 or 2.

In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof is a compound, wherein R ^1a is selected from the group consisting of: , and The subscript q is 0, 1 or 2.

In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof is a compound, wherein R ^1a is selected from the group consisting of: and The subscript q is 0, 1 or 2.

In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof is a compound, wherein R ^1a is selected from the group consisting of: The subscript q is 0, 1 or 2.

In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof is a compound, wherein R ^1a is selected from the group consisting of: The subscript q is 0, 1 or 2.

In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof is a compound, wherein R ^1a is selected from the group consisting of: , , , , , and , where q is 0 or 1.

In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof is a compound, wherein R ^1a is selected from the group consisting of: , , , , , ,and , each of which is replaced by an additional R ⁴ as appropriate.

In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof is a compound, wherein R ^1a is selected from the group consisting of: , and .

In some embodiments, the heteroaryl moiety in R ^1a includes groups substituted with one or more pendant oxy substituents following Huckel's rule. Therefore, in some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof is a compound in which the heteroaryl group of R ^1a includes a pendant oxygen group bonded to the same ring apex. Two R ⁴ groups of the base (=O). Exemplary groups include, but are not limited to, pyridinonyl and pyridinonyl. Therefore, in some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof is a compound in which R 1a and R ^1a are combined on the same ring vertex to form a pendant oxygen group (=O ), the two R ⁴ groups together form a heteroaryl moiety selected from the group consisting of pyridinonyl and pyridinonyl, wherein R ^1a is substituted with 0 to 2 additional R ⁴ groups.

In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof is a compound, wherein R ^1a includes 2-4 R ⁴ moieties and is selected from the group consisting of: , and , where the subscript q is 0, 1 or 2.

In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof is a compound, wherein R ⁴ is independently selected from the group consisting of: C _1-7 alkyl, Halo group, C _1-7 haloalkyl group, -OC 1-7 alkyl group, -OC _1-7 haloalkyl group, CN, _{-C 1-7 alkylene} group-CN, hydroxyl group, C _1-7 hydroxyalkyl group , -C(O)NR ^a R ^b , C _3-7 cycloalkyl, -NR ^a -C(O)-C _1-7 alkyl, -NR ^a -C(O)-C _3-7 cycloalkyl base, -NR ^a R ^b , -OC _1-4 alkylene group -OC _1-4 alkyl group, -O-(5 with 1-3 heteroatom ring vertices selected from the group consisting of O, N and S to 8-membered heterocycloalkyl), -5 to 8-membered heterocycloalkyl having 1-3 heteroatom ring vertices selected from the group consisting of O, N and S, -S(O) ₂ -C _{1- 7} alkyl, -S(O) ₂ -C _3-7 cycloalkyl, -S(O) ₂ -NR ^a R ^b , -NR ^a -S(O) ₂ -C _1-7 alkyl and -NR ^a -S(O) ₂ -C _3-7 cycloalkyl, wherein each C _3-7 cycloalkyl, -NR ^a -C(O)-C _3-7 cycloalkyl, -S(O) ₂ - C _3-7 cycloalkyl, -NR ^a -S(O) ₂ -C _3-7 cycloalkyl, -O-(5 to 8 membered heterocycloalkyl) and -5 to 8 membered heterocycloalkyl 0 to 2 substituted groups independently selected from the group consisting of: C _1-4 alkyl, halo and hydroxyl.

In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate or solvate thereof, is a compound wherein each R ⁴ , when present, is independently selected from the group consisting of: C _{1- 4} alkyl, halo, C _1-4 haloalkyl, -OC _1-4 alkyl, -OC _1-4 haloalkyl, CN, -C _1-4 alkyl-CN, C _1-4 hydroxyl Alkyl group, -C(O)NR ^a R ^b , C _3-7 cycloalkyl group, -NR ^a -C(O)-C _3-7 cycloalkyl group, -NR ^a R ^b , -OC _1-4 cycloalkyl group Alkyl -OC _1-4 alkyl, -O- (5 to 6 membered heterocycloalkyl) with 1-3 heteroatom ring vertices selected from the group consisting of O, N and S, -S(O) ₂ -C _1-4 alkyl and -S(O) ₂ -NR ^a R ^b , wherein each cycloalkyl and heterocycloalkyl is substituted by 0 to 2 groups selected from the group consisting of: C _{1- 4} alkyl group, halo group and hydroxyl group; or two R ⁴ groups combined on the same ring vertex to form a side oxygen group (=O).

In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate or solvate thereof, is a compound wherein each R ⁴ , when present, is independently selected from the group consisting of: C _{1- 4} alkyl, halo, C _1-4 haloalkyl, -OC _1-4 alkyl, -OC _1-4 haloalkyl, CN, -C _1-4 alkyl-CN, C _1-4 hydroxyl Alkyl group, -C(O)NR ^a R ^b , C _3-7 cycloalkyl group, -NR ^a -C(O)-C _3-7 cycloalkyl group, -NR ^a R ^b , -OC _1-4 cycloalkyl group Alkyl -OC _1-4 alkyl, -O- (5 to 6 membered heterocycloalkyl) with 1-3 heteroatom ring vertices selected from the group consisting of O, N and S, with 1-3 -5 to 8-membered heterocycloalkyl, -S(O) ₂ -C _1-4 alkyl and -S(O) ₂ -NR ^a R at the vertex of the heteroatom ring selected from the group consisting of O, N and S ^b , wherein each cycloalkyl and heterocycloalkyl is substituted by 0 to 2 groups selected from the group consisting of: C _1-4 alkyl, halo and hydroxyl; or, combined on the same ring vertex to form a side oxygen Two R ⁴ groups of the base (=O).

In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate or solvate thereof, is a compound wherein each R ⁴ , when present, is independently selected from the group consisting of: C _{1- 4} alkyl, halo, C _1-4 haloalkyl, -OC _1-4 alkyl, -OC _1-4 haloalkyl, CN, -C _1-4 alkyl-CN, C _1-4 hydroxyl Alkyl group, -C(O)NR ^a R ^b , C _3-7 cycloalkyl group, -NR ^a -C(O)-C _3-7 cycloalkyl group, -NR ^a R ^b , -OC _1-4 cycloalkyl group Alkyl -OC _1-4 alkyl, -O- (5 to 6 membered heterocycloalkyl) with 1-3 heteroatom ring vertices selected from the group consisting of O, N and S, -S(O) ₂ -C _1-4 alkyl, -S(O) ₂ -NR ^a R ^b , wherein each cycloalkyl and heterocycloalkyl is substituted by 0 to 2 groups selected from the group consisting of: C _{1- 4Alkyl} , halo and hydroxyl groups.

In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate or solvate thereof, is a compound wherein each R ⁴ , when present, is independently selected from the group consisting of: C _{1- 4} alkyl, halo, C _1-4 haloalkyl, -OC _1-4 alkyl, -OC _1-4 haloalkyl, CN, -C _1-4 alkyl-CN, C _1-4 hydroxyl Alkyl group, -C(O)NR ^a R ^b , C _3-7 cycloalkyl group, -NR ^a -C(O)-C _3-7 cycloalkyl group, -NR ^a R ^b , -OC _1-4 cycloalkyl group Alkyl -OC _1-4 alkyl, -O- (5 to 6 membered heterocycloalkyl) with 1-3 heteroatoms selected from the group consisting of O, N and S at the ring vertex, with 1-3 -5 to 8-membered heterocycloalkyl, -S(O) ₂ -C _1-4 alkyl, -S(O) ₂ -NR ^a R at the vertex of the heteroatom ring selected from the group consisting of O, N and S ^b , wherein each cycloalkyl and heterocycloalkyl is substituted by 0 to 2 groups selected from the group consisting of: C _1-4 alkyl, halo and hydroxyl.

In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate or solvate thereof, is a compound, wherein each R ⁴ when present is independently selected from the group consisting of: methyl, Ethyl, fluorine, chlorine, difluoromethyl, trifluoromethyl, CN, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, , , , , , , , , , , , , , , , , and .

In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate or solvate thereof, is a compound wherein each R ⁴ when present is independently methyl. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate or solvate thereof, is a compound wherein each R ⁴ when present is independently ethyl. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate or solvate thereof, is a compound wherein each R ⁴ when present is independently fluorine. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate or solvate thereof, is a compound wherein each R ⁴ when present is independently chloro. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate or solvate thereof, is a compound wherein each R ⁴ when present is independently CN.

In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt, hydrate or solvate thereof, is a compound in which two R ⁴ groups on adjacent ring vertices combine to form a compound having 1 to 2 A 5- to 6-membered heterocycloalkyl group at the vertex of a heteroatom ring selected from the group consisting of O, N and S, wherein the 5- to 6-membered heterocycloalkyl group is separated by 0 to 2 independently selected from the group consisting of Group substitution: C _1-4 alkyl and halo.

In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof is a compound in which two R ⁴ groups on adjacent ring vertices combine to form a compound selected from the group consisting of: Heterocycloalkyl: and wherein the heterocycloalkyl group is substituted with 0 to 2 groups independently selected from the group consisting of: C _1-4 alkyl and halo. In some embodiments, heterocycloalkyl is substituted with a C _1-4 alkyl.

In some embodiments, a compound of formula (I), or a pharmaceutically acceptable salt, hydrate or solvate thereof, is a compound, wherein A has a formula selected from the group consisting of: , each of which is further substituted by 0 to 2 independently selected R ² groups.

In some embodiments, a compound of formula (I), or a pharmaceutically acceptable salt, hydrate or solvate thereof, is a compound, wherein A has the formula: .

In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt, hydrate or solvate thereof, is a compound wherein R ² attached to the nitrogen is selected from the group consisting of: C _1-7 alkane base, C _3-6 cycloalkyl, -Y ¹ -OC _1-4 alkyl, -Y ¹ -OC _3-7 cycloalkyl, -C(O)-C _1-7 alkyl, -C(O )-C _3-7 cycloalkyl, 5 to 8 membered heterocycloalkyl, -C(O)-(5 to 8 membered heterocycloalkyl) and -X ¹ -(5 to 8 membered heterocycloalkyl) , wherein the heterocycloalkyl group has 1-3 heteroatom ring vertices selected from the group consisting of O, N and S, and wherein the cycloalkyl group and the heterocycloalkyl group have 0-3 groups independently selected from the following groups Substitution: halo, CN, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 hydroxyalkyl, -OC _1-4 alkyl and OH.

In some embodiments, a compound of formula (I), or a pharmaceutically acceptable salt, hydrate or solvate thereof, is a compound of formula (Ia): (Ia).

In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof is a compound of formula (Ia1): (Ia1).

In some embodiments, a compound of formula (I), or a pharmaceutically acceptable salt, hydrate or solvate thereof, is a compound of formula (Ib): (Ib) wherein the subscript m is 0 or 1; and n is 0, 1 or 2, and each R ² may be the same or different.

In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof is a compound of formula (Ib1): (Ib1) wherein the subscript m is 0 or 1; and n is 0, 1 or 2, and each R ² can be the same or different.

In some embodiments, a compound of formula (I), or a pharmaceutically acceptable salt, hydrate or solvate thereof, is a compound of formula (Ic): (Ic) wherein R ⁶ is selected from the group consisting of halo, CN, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 hydroxyalkyl, -OC _1-4 alkyl, side Oxygen group and OH.

In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof is a compound of formula (Ic1): (Ic1) wherein R ⁶ is selected from the group consisting of halo, CN, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 hydroxyalkyl, -OC _1-4 alkyl, side Oxygen group and OH.

In some embodiments, a compound of formula (I), or a pharmaceutically acceptable salt, hydrate or solvate thereof, is a compound of formula (Id): (Id).

In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof is a compound of formula (Id1): (Id1).

In some embodiments, a compound of formula (I), or a pharmaceutically acceptable salt, hydrate or solvate thereof, is a compound of formula (Ie): (Ie) wherein the subscript n is 0, 1 or 2, and each R ² may be the same or different.

In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, hydrate or solvate thereof, is a compound of formula (Ie1): (Ie1) where the subscript n is 0, 1 or 2, and each R ² can be the same or different.

In some embodiments, a compound of formula (I), or a pharmaceutically acceptable salt, hydrate or solvate thereof, is a compound of formula (If): (If).

In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof is a compound of formula (If1): (If1).

In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate or solvate thereof, is a compound, wherein m is 0.

In some embodiments, a compound of formula (I), or a pharmaceutically acceptable salt, hydrate or solvate thereof, is a compound wherein n is 0.

In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, hydrate or solvate thereof, is a compound of formula (II): (II) Or a pharmaceutically acceptable salt thereof, wherein: X is CH or N; G ¹ is N or CH; A is a fused ring selected from the group consisting of: cycloheptane, cyclohexane and nitrogen Heterocycloheptanes, each of which is substituted with 1 to 4 ^R2 ; ^R1 is selected from the group consisting of phenyl and 5 of the ring vertices having 1 to 3 heteroatoms selected from the group consisting of O, N and S to a 6-membered heteroaryl group, and each phenyl and heteroaryl group is substituted by one R ^1a and 0-3 R ³ ; R ^1a is selected from the group consisting of: phenyl and has 1-3 selected from O, A 5- to 6-membered heteroaryl group at the vertex of the heteroatom ring of a group consisting of N and S, in which the N atom is optionally oxidized when present, and each phenyl and heteroaryl group is substituted by 0-4 R ⁴ ; each R ² is independently selected from the group consisting of: C _1-7 alkyl, C _3-7 cycloalkyl, -Y ¹ -OC _1-7 alkyl, -NR ^a R ^b , 5- to 8-membered heterocycloalkanes and -NR ^a -(5 to 8 membered heterocycloalkyl), wherein the heterocycloalkyl group has 1-3 heteroatom ring vertices selected from the group consisting of O, N and S, and wherein each cycloalkyl group and Heterocycloalkyl is substituted with 0-3 groups independently selected from the group consisting of: C _1-4 alkyl and -OC _1-4 alkyl; each R ³ is independently selected from the group consisting of halo, C _1-7 alkyl and -OC _1-7 alkyl; each R ⁴ is independently selected from the group consisting of: C _1-7 alkyl, halo, C _1-7 haloalkyl, -OC _1-7 alkyl base, -OC _1-7 haloalkyl, CN, -C _1-7 alkylene-CN, C _1-7 hydroxyalkyl, -C(O)NR ^a R ^b , C _3-7 cycloalkyl, -NR ^a -C(O)-C _3-7 cycloalkyl, -NR ^a R ^b , -OC _1-4 alkylene group -OC _1-4 alkyl, having 1-3 selected from O, N and -O- (5 to 8-membered heterocycloalkyl) at the vertex of the heteroatom ring selected from the group consisting of S, -5 to 8 members at the vertex of the heteroatom ring having 1-3 selected from the group consisting of O, N, and S Heterocycloalkyl, -S(O) ₂ -C _1-7 alkyl and -S(O) ₂ -NR ^a R ^b , wherein each cycloalkyl and heterocycloalkyl is independently selected from 0 to 2 The following groups are substituted: C _1-4 alkyl and hydroxyl; alternatively, two R ⁴ groups on adjacent ring vertices are combined to form a heteroatom ring with 1 to 2 selected from the group consisting of O, N and S A 5- to 6-membered heterocycloalkyl group at the vertex, wherein the 5- to 6-membered heterocycloalkyl group is substituted by 0 to 2 C _1-4 alkyl groups; each X ¹ is a C 1-7 alkyl group; each Y ¹ is a C _1-7 alkyl group; C _2-7 alkyl; each R ^a and R ^b are independently selected from the group consisting of: H, C _1-7 alkyl, C _3-7 cycloalkyl, wherein the cycloalkyl is optionally modified by -OC _1-3 alkyl substitution; or R ^a and R ^b together with the nitrogen to which they are attached form a 4- to 8-membered heterocycloalkane having 0-2 additional heteroatom ring vertices selected from the group consisting of O, N and S base ring, wherein the heterocycloalkyl ring is substituted by 0-3 groups, each group is independently selected from C _1-4 alkyl, -OC _1-4 alkyl and X ¹ -OC _1-3 alkyl ; Or two groups on the vertex of the same ring combine to form a side oxygen group (=O).

In some selected embodiments, any of the compounds described in the examples or a pharmaceutically acceptable salt, solvate or hydrate thereof is provided. In some embodiments, any one of the compounds described in the examples or a pharmaceutically acceptable salt thereof is provided. In further embodiments, any of the compounds described in the Examples are provided. Methods for Preparing Compounds of the Disclosure

In some aspects, the present disclosure relates to methods for preparing compounds that inhibit the activity of AXL.

In some embodiments, the present disclosure relates to a method comprising: a) contacting a compound of formula (A) with a compound of formula (B) in the presence of a first palladium catalyst to form a compound of formula (C): ; and b) contacting a compound of formula (C) with a deprotecting agent to form a compound of formula (D): ; wherein X, G ¹ , R ¹ , R ^1a and R ² are as defined herein; Q is N, CH or CR ² ; PG is a protecting group; and one of Y and Z is Cl, Br, I or OTf, and the other is a borate ester.

In another embodiment, the present disclosure relates to a method comprising: a) contacting a compound of formula (E) with a compound of formula (B-2) in the presence of a first palladium catalyst to form a compound of formula (C): ; and b) contacting a compound of formula (C) with a deprotecting agent to form a compound of formula (D): ; wherein X, G ¹ , R ¹ , R ^1a and R ² are as defined herein; Q is N, CH or CR ² ; PG is a protecting group; and one of Y' and Z' is Cl, Br, I or OTf, and the other is a borate ester.

Any suitable borate ester can be used. Exemplary borates include, but are not limited to, pinacolborane (Bpin), catecholborane, and N-methyliminodiacetate borane (MIDA borane). In some embodiments, _the boronic acid ^ester is of _{the formula} ^-B ( ^OR The atoms come together to form pinacolborane (Bpin). In one embodiment, the borate ester is Bpin.

The term "protecting group" refers to a portion of a compound that masks or changes the properties of a functional moiety. The protective group can be removed to restore the functional part to its original state. Chemical protecting groups and protection/deprotection strategies are well known in the art. See also Protective Groups in Organic Chemistry , Peter GM Wuts and Theodora W. Greene, 4th ed., 2006. Protecting groups are often used to mask the reactivity of certain functional moieties to help increase the efficiency of desired chemical reactions, for example, forming and breaking chemical bonds in an orderly and planned manner. For example, a nitrogen protecting group refers to a protecting group that can be used to mask nitrogen atoms, such as rendering amines or nitrogen-containing heteroaromatics unreactive during intermediate steps. Exemplary nitrogen protecting groups include, but are not limited to, allyloxycarbonyl (Alloc), benzylcarbonyl (Cbz), benzyl (Bz), allyl (All), 2,2,2-trichloroethoxy Carbonyl (Troc), 2-(trimethylsilyl)ethoxycarbonyl (Teoc), trityl (Tr), tetrahydropyranyl ether (THP) and sulfonyl (for example, methanesulfonyl group (Ms), p-toluenesulfonyl group (Ts), nitrobenzene sulfonyl group (Ns), trifluoromethanesulfonyl group (Tf) and phenylene sulfonyl group (-S(O) ₂ Ph)). In some embodiments, the protecting group is phenylene (-S(O) ₂ Ph), p-toluenesulfonyl (Ts), trityl (Tr), 2-(trimethylsilyl)ethoxy methyl (SEM) or tetrahydropyranyl ether (THP).

"Deprotecting agents" are chemical reactants that can affect the removal of protecting groups. The deprotecting agent used will depend, for example, on the nature of the protecting group to be removed, and the reactivity of other functional groups present on the molecule. Typical deprotecting agents include reducing agents, oxidizing agents, acids, Lewis acids, bases, fluoride reagents and enzymes. Generally speaking, ether protecting groups can be removed under acidic conditions; alkyl protecting groups can be removed under reducing conditions or by treatment with Lewis acids; trityl protecting groups can be removed under acidic conditions or by treatment with Lewis acids The acyl protecting group can be removed under reducing conditions, under alkaline conditions, or by treatment with an enzyme; and the benzyl protecting group can be removed under reducing conditions or by treatment with Lewis acid. Exemplary reducing agents include, but are not limited to, hydrogen, metal hydrides (eg, diisobutylaluminum hydride (DIBAL) and lithium aluminum hydride (LAH)), or borohydrides (eg, sodium borohydride). Exemplary bases include, but are not limited to, ammonia, methylamine, sodium methoxide, metal hydroxides (eg, LiOH, NaOH, and KOH), and the like. Exemplary acids include, but are not limited to, HCl, formic acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, and the like. Exemplary Lewis acids include, but are not limited to, _ZnCl2 , _ZnBr2 , _TiCl4 , _BF3 , trimethylsilyl iodide (TMSI), and the like. Exemplary oxidizing agents include, but are not limited to, dicyanodichloroquinone (DDQ), triethylenediamine (DABCO), poly(4-vinylpyridinium tribromide), hydrogen peroxide, and the like. Exemplary enzymes include, but are not limited to, ester hydrolases or lipases.

In some embodiments, the protecting group is -S(O) _2Ph or p-toluenesulfonyl (Ts), and the deprotecting agent is a base (eg, NaOH). In another embodiment, the protecting group is tetrahydropyranyl ether (THP), trityl (Tr) or 2-(trimethylsilyl)ethoxymethyl (SEM), and deprotection The agent is an acid (for example, trifluoroacetic acid). In some embodiments, the deprotecting agent further comprises a silane (eg, triethylsilane or trimethylsilane) or an amine (eg, _NH3 or N,N -dimethylethylenediamine).

Any suitable palladium catalyst may be used in the preparation of compounds of formula (C). Exemplary palladium catalysts that can be used include, but are not limited to, [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (PdCl ₂ (dppf)), palladium(II) acetate (Pd (OAc) ₂ ), tetrakis(triphenylphosphine)palladium(0) (Pd(PPh ₃ ) ₄ ), dichloro(1,5-cyclooctadiene)palladium(II) ((COD)PdCl ₂ ), Bis[1,2-bis(diphenylphosphino)ethane]palladium(0) (Pd(dppe) ₂ ), bis(triphenylphosphine)palladium(II) dichloride ((PPh3) ₂ PdCl ₂ ), (2-dicyclohexylphosphine-2′,6′-dimethoxybiphenyl) [2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate ) (SPhos Pd G3), (2-dicyclohexylphosphine-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1, 1′-biphenyl)]palladium(II) methanesulfonate (XPhos Pd G3), dibenzylideneacetone dipalladium(0) (Pd ₂ (dba) ₃ ) and the like. In one embodiment, the palladium catalyst is PdCl ₂ (dppf).

In some embodiments, the method further comprises contacting the compound of formula (A) and the compound of formula (B) in the presence of a first palladium catalyst and a base. Any suitable base can be used. Exemplary bases include, but are not limited to, sodium carbonate, potassium carbonate, potassium acetate, sodium acetate, sodium hydroxide, potassium hydroxide, potassium tertiary butoxide, sodium tertiary butoxide, and the like. In some embodiments, the base is sodium carbonate, potassium carbonate, or potassium acetate.

In one or more embodiments, a compound of formula (B) is formed by contacting a compound of formula (B-1) and a compound of formula (B-2) in the presence of a second palladium catalyst: ; Among them, one of Y' and Z' is Cl, Br, I or OTf, and the other is a borate ester; and PG is a protecting group. The remaining variables have the above identification.

Generally speaking, Y, Y' and Z' are chosen such that Y' and Z' are better coupling partners than Y' and Y. For example, when Y' is a boronic acid ester and Y and Z' are each Cl, Br, I or OTf, preferably Z' is more reactive than Y. In some embodiments, Y' is a boronic acid ester; Z' is I or OTf; and Y is Cl or Br. In one embodiment, Y' is a boronic acid ester; Z' is I; and Y is Br.

In other embodiments, a compound of formula (E) is formed by contacting a compound of formula (A) and a compound of formula (B-1) in the presence of a second palladium catalyst: ; wherein one of Y and Z is Cl, Br, I or OTf, and the other is a borate ester; and PG is a protecting group. The remaining variables have the above identification.

Generally speaking, Y, Z and Z' are chosen such that Y and Z are better coupling partners than Z and Z'. For example, when Z is a boronic acid ester and Y and Z' are each Cl, Br, I or OTf, preferably Y is more reactive than Z'. In some embodiments, Z is a boronic acid ester, Y is I or OTf, and Z' is Cl or Br. In one embodiment, Z is a boronic acid ester; Y is I; and Z' is Br.

In one or more embodiments, the boronic acid ester is part of the formula -B( ^ORx ) ₂ , wherein each ^Rx is H or _C1 - _C3 alkyl, or two ^-ORx groups are combined with The linked boron atoms together form pinacolborane (Bpin). In one embodiment, the borate ester is Bpin.

Any suitable palladium catalyst may be used in the preparation of compounds of formula (B). Exemplary palladium catalysts that can be used include, but are not limited to, [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (PdCl ₂ (dppf)), palladium(II) acetate (Pd (OAc) ₂ ), tetrakis(triphenylphosphine)palladium(0) (Pd(PPh ₃ ) ₄ ), dichloro(1,5-cyclooctadiene)palladium(II) ((COD)PdCl ₂ ), Bis[1,2-bis(diphenylphosphino)ethane]palladium(0) (Pd(dppe) ₂ ), bis(triphenylphosphine)palladium(II) dichloride ((PPh3) ₂ PdCl ₂ ), (2-dicyclohexylphosphine-2′,6′-dimethoxybiphenyl) [2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate ) (SPhos Pd G3), (2-dicyclohexylphosphine-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1, 1′-biphenyl)]palladium(II) methanesulfonate (XPhos Pd G3), dibenzylideneacetone dipalladium(0) (Pd ₂ (dba) ₃ ) and the like. In one embodiment, the palladium catalyst is PdCl ₂ (dppf).

In one or more embodiments, G ¹ is N. In certain such embodiments, a compound of formula (B) can be formed by contacting a compound of formula (B-3) with hydrazine or a hydrate thereof: ; wherein Z ^a is a halo group; and m is 0 or 1. In some embodiments, Z ^a is F. The remaining variables have the identifiers defined above.

In one or more embodiments, a compound of formula (B-3) is prepared by: a) contacting a compound of formula (B-4) with a lithiation reagent to form a compound of formula (B-5): ; and b) contact the compound of formula (B-5) with the compound of formula (B-6): ; Where R ^o is H or C ₁ -C ₃ alkyl. The remaining variables have the identifiers defined above.

Any suitable lithiation reagent can be used. Exemplary lithiation reagents include, but are not limited to, lithium diisopropylamide (LDA), lithium 2,2,6,6-tetramethylpiperidine (LTMP), lithium dicyclohexylamide, lithium dimethylamine Lithium, lithium diethylamide, lithium amide, lithium bis(trimethylsilyl)amide and the like. In some embodiments, the lithiation reagent is LDA.

In a further embodiment, a compound of formula (B-3) is prepared by: contacting a compound of formula (B-7) with a compound of formula (B-8): ; Where Q ¹ is halo, -CN, -C(O)OH, -C(O)O-(C ₁ -C ₃ alkyl), -C(O)Cl or -C(O)N(C ₁ -C ₃ alkyl)-O-(C ₁ -C ₃ alkyl); Q ² is -Li, -Mg-halo or -B(OR ^x ) ₂ ; and each R ^x is H or C ₁ - A C _alkyl group, or two -OR ^x groups together with the boron atom to which they are attached form pinacolborane (Bpin). The remaining variables have the identifiers defined above.

In some embodiments, Q ¹ is -Cl, -Br, -I, -CN, -C(O)OH, -C(O)OCH ₃ , -C(O)Cl or -C(O)N( CH ₃ )OCH ₃ . In some embodiments, Q ^is -Li, -MgCl, -MgBr, -B(OH), _or -Bpin.

In further embodiments, Q ¹ is -CN, -C(O)OH, -C(O)OCH ₃ , -C(O)Cl or -C(O)N(CH ₃ )O(CH ₃ ), And Q ² is -Li, -MgCl or -MgBr. In certain embodiments, Q ¹ is -CN, Q ² is -MgCl or -MgBr, and the method further includes adding water.

In further embodiments, Q ¹ is -C(O)Cl, Q ² is -B(OR ^x ) ₂ (e.g., B(OH) ₂ or -Bpin), and the method further comprises adding a palladium catalyst, such as herein They are described elsewhere.

In yet further embodiments, Q ¹ is halo (eg, -Cl, -Br or -I), Q ² is -Li, -MgCl or -MgBr, and the method further comprises adding CO and a palladium catalyst, such as herein They are described elsewhere.

In order to most efficiently prepare any particular compound of the present disclosure, the timing and order of attachment of the fragments, as well as modification of the functionality present in any fragment, can vary and will depend on the functionality present. The various methods described above have been used to prepare the compounds of the present disclosure and are exemplified in the following Examples. Deuterated forms of the following examples can be synthesized using appropriate deuterated intermediates. Therapeutic and preventive uses

The present disclosure provides methods of using the compounds described herein in the preparation of medicaments for inhibiting AXL. As used herein, the terms "inhibit," "inhibition," and the like refer to the ability of an antagonist to reduce the function or activity of a specific target, such as AXL. The reduction is preferably at least 50%, and may be, for example, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90 % or at least about 95%. The present disclosure also encompasses the use of a compound described herein in the preparation of a medicament for the treatment or prevention of diseases, conditions and/or disorders that would benefit from inhibition of AXL. As one example, the present disclosure encompasses the use of a compound described herein in the preparation of a medicament for treating cancer. In another embodiment, the present disclosure contemplates the use of a compound described herein in the preparation of a medicament for the treatment of fibrotic diseases. In another embodiment, the present disclosure encompasses the use of a compound described herein in the preparation of a medicament for treating viral infections. In some embodiments of the above methods, a compound described herein is used in combination with at least one additional therapy, examples of which are described elsewhere herein.

AXL is expressed in cancer, selected immune cells, and stromal cells, and is implicated in the development of resistance/relapse to chemotherapy, radiation therapy, targeted therapy, and immunotherapy. AXL is activated by its ligand, growth arrest-specific protein 6 (GAS6), or ligand-independent dimerization, thereby promoting AXL phosphorylation and initiating a signaling cascade that promotes cancer cell proliferation, survival, and immunosuppressive microenvironment. reaction. Therefore, inhibition of AXL is a promising therapeutic strategy to overcome resistance to chemotherapy, radiotherapy, targeted therapy and/or immunotherapy.

As demonstrated herein, compounds according to the disclosure effectively inhibit AXL. Diseases, conditions and/or disorders that would benefit from AXL inhibition may include those characterized by overexpression of AXL.

Accordingly, in some embodiments, a compound described herein is administered to an individual in need thereof in an amount effective to inhibit AXL. AXL inhibition can be assessed by measuring soluble AXL (sAXL) levels or AXL expression in plasma, or phospho-AXL (pAXL) levels in peripheral blood samples or tissue samples obtained from an individual (e.g., tumor samples). For example, activity can be determined by comparison with a previous sample obtained from the individual (i.e., prior to administration of the AXL inhibitor), or by comparison with a reference value for a control group (e.g., standard of care, placebo, etc.) .

Alternatively or additionally, in some embodiments, a compound described herein is administered to an individual in need thereof in an amount effective to inhibit AXL phosphorylation. Inhibition of AXL phosphorylation (pAXL) can be assessed by measuring pAXL expression in peripheral blood samples or tissue samples (e.g., tumor samples) obtained from the individual. For example, by comparison with a previous sample obtained from the individual (i.e., prior to administration of a compound of the present disclosure), or by comparison with a reference value for a control group (e.g., standard of care, placebo, etc.) Determine activity. Inhibition of pAXL can also be assessed by measuring levels of sAXL, GAS6, or other factors in serum or plasma obtained from the individual.

Alternatively or additionally, in some embodiments, a compound described herein is administered to an individual in need thereof to treat and/or prevent cancer or cancer-related diseases, conditions or disorders. In some embodiments, a compound described herein is administered to an individual in need thereof to treat cancer, optionally in combination with at least one additional therapy, examples of which are set forth elsewhere herein.

Alternatively or additionally, in some embodiments, a compound described herein is administered to an individual in need thereof to treat and/or prevent viral infection, as described in further detail below.

Alternatively or additionally, in some embodiments, a compound described herein is administered to an individual in need thereof to treat and/or prevent a fibrotic disease, condition or disorder, as described in further detail below.

Alternatively or additionally, in some embodiments, a compound described herein is administered to an individual in need thereof to treat and/or prevent pain, as described in further detail below.

Alternatively or additionally, in some embodiments, a compound described herein is administered to an individual in need thereof to treat and/or prevent an immune-related disease, condition or disorder.

In specific embodiments of the present disclosure, the compounds are used to increase or enhance the immune response to tumors or viral infections. In one embodiment, at least one antigen or vaccine is administered to an individual in combination with at least one compound of the present disclosure to prolong the immune response to the antigen or vaccine. Therapeutic compositions are also provided, which include at least one antigenic agent or vaccine component (including but not limited to viruses, bacteria and fungi, or parts thereof, proteins, peptides, tumor-specific antigens and nucleic acid vaccines) and at least one agent of the present disclosure. combination of compounds.

Oncology and oncology-related conditions. In one or more embodiments, the compounds described herein may be used to treat and/or prevent cancer (eg, carcinoma, sarcoma, leukemia, lymphoma, myeloma, etc.). In certain embodiments, the cancer may be locally advanced and/or unresectable, metastatic, or at risk of metastasis. Alternatively, or in addition, the cancer may recur or no longer respond to treatment, such as standard of care treatments known to those skilled in the art. Exemplary cancer types covered by this disclosure include genitourinary tract cancers (e.g., bladder cancer, kidney cancer, renal cell carcinoma, penile cancer, prostate cancer, testicular cancer, ovarian cancer, cervical cancer, uterine cancer, Von Hippel-Lindau diseases, etc.), breast cancer, gastrointestinal cancer (e.g., esophagus, oropharynx, stomach, small or large intestine, colon, or rectum), bone cancer, bone marrow cancer, skin cancer (e.g., melanoma, squamous cell or basal cell carcinoma), head and neck cancer, liver cancer, gallbladder cancer, cholangiocarcinoma, heart cancer, lung cancer, pancreatic cancer, salivary gland cancer, adrenal gland cancer, thyroid cancer, brain cancer (e.g., glioma), ganglion cancer, central nervous system cancer Nervous system (CNS) cancers, peripheral nervous system (PNS) cancers, hematopoietic system cancers (i.e., blood malignancies), and immune system cancers (e.g., spleen cancer or thymus cancer). In some embodiments, the patient with cancer is determined to have an STK11 mutation.

In some embodiments, compounds according to the present disclosure can be used to treat and/or prevent hematological malignancies. Exemplary cancer types affecting the hematopoietic system include leukemias, lymphomas, and myeloma, including acute myelogenous leukemia, adult T-cell leukemia, T-cell large granular lymphocytic leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia leukemia, acute monocytic leukemia, Hodgkin's and non-Hodgkin's lymphoma, diffuse large B-cell lymphoma and multiple myeloma. In some embodiments, the hematological malignancy is acute myelogenous leukemia.

In another embodiment, compounds according to the present disclosure may be used to treat and/or prevent solid tumors. Solid tumors may be, for example, ovarian cancer, fallopian tube cancer, primary peritoneal cancer, endometrial cancer, breast cancer, lung cancer (small cell or non-small cell), colon cancer, prostate cancer, cervical cancer, biliary tract cancer, pancreatic cancer , stomach cancer, esophageal cancer, liver cancer (hepatocellular carcinoma), kidney cancer (renal cell carcinoma), head and neck tumors, mesothelioma, melanoma, sarcoma, central nervous system (CNS) hemangioblastoma, and brain tumors ( e.g. , Glioma, such as astrocytoma, oligodendroglioma, and glioblastoma).

In some embodiments, compounds according to the present disclosure can be used to treat lung cancer (e.g., non-small cell lung cancer (NSCLC)), pancreatic cancer (e.g., pancreatic ductal adenocarcinoma (PDAC)), ovarian cancer (e.g., epithelial ovarian cancer (EOC), high-grade serous ovarian cancer (HSOC), or platinum-resistant ovarian cancer (PROC)), breast cancer (eg, triple-negative breast cancer (TNBC)), bladder cancer, head and neck cancer (eg, head and neck squamous cell carcinoma) nephrotic cell carcinoma (HNSCC)), kidney cancer (e.g., clear cell renal cell carcinoma (ccRCC)), liver cancer, glioblastoma, mesothelioma, melanoma, or leukemia (e.g., acute myeloid leukemia (AML) or Myelodysplasia syndrome). In some embodiments, the cancer is lung cancer, pancreatic cancer, ovarian cancer, breast cancer, head and neck cancer, renal cancer, leukemia, or myeloid metaplasia syndrome. In one embodiment, the cancer is NSCLC, PDAC, ccRCC or AML.

In some embodiments, compounds according to the present disclosure can be used to treat kidney cancer. In further embodiments, the renal cancer is renal cell carcinoma. In a further embodiment, the renal cell carcinoma is clear cell renal cancer (ccRCC).

In some embodiments, compounds according to the present disclosure can be used to treat lung cancer. In a further embodiment, the lung cancer is non-small cell lung cancer (NSCLC). In a further embodiment, the NSCLC is lung squamous cell carcinoma or lung adenocarcinoma. In some embodiments, the NSCLC is EGFR mutant NSCLC. In some embodiments, the NSCLC is STK11 mutant NSCLC. In some embodiments, NSCLC has relapsed and requires treatment, including but not limited to anti-PD-L1 or other immunotherapy, targeted therapy, or chemotherapy. In some embodiments, the lung cancer is squamous cell carcinoma (SCC).

In some embodiments, compounds according to the present disclosure can be used to treat head and neck cancer. In a further embodiment, the head and neck cancer is head and neck squamous cell carcinoma (HNSCC). In some embodiments, HNSCC relapses or is resistant to radiation, chemotherapy, or immunotherapy.

In some embodiments, compounds according to the present disclosure can be used to treat leukemia or myelodysplasia syndrome (MDS). In a further embodiment, the leukemia is acute myelogenous leukemia (AML). In a further embodiment, the AML or MDS is relapsed or refractory AML or MDS. In some embodiments, the AML is FLT-3 mutant AML.

In some embodiments, compounds according to the present disclosure can be used to treat breast cancer. In further embodiments, the breast cancer is hormone receptor positive (eg, ERα positive breast cancer, PR positive breast cancer, ERα positive and PR positive breast cancer), HER2 positive breast cancer, HER2 overexpressing breast cancer, or any combination thereof. In a further embodiment, the breast cancer is triple negative breast cancer (TNBC).

In some embodiments, compounds according to the present disclosure can be used to treat pancreatic cancer. In a further embodiment, the pancreatic cancer is a pancreatic neuroendocrine tumor (PNET) or pancreatic cancer (ie, pancreatic ductal adenocarcinoma (PDAC)).

In some embodiments, compounds according to the present disclosure can be used to treat ovarian cancer. In further embodiments, the ovarian cancer is metastatic. In further embodiments, the ovarian cancer is epithelial ovarian cancer (EOC). In some embodiments, the ovarian cancer is high-grade serous ovarian cancer (HGSOC). In some embodiments, the ovarian cancer is characterized by a mesenchymal (MES) molecular subtype. In some embodiments, ovarian cancer is resistant to therapies including, but not limited to, platinum- or taxane-based therapies (eg, platinum-resistant ovarian cancer (PROC)).

In one or more embodiments, the cancer is an oncogene-addicted cancer. Oncogene-addicted cancers are those that depend on dominant oncogenes for growth and survival, such as ALK, ABL, AURORA, AKT, PDGFR, KIT, EGFR, VEGFR, FGFR3, FLT-3, MYC, RET, BRAF, PI3K, NF-κB, JAK, STAT, BCL-2, MCL-1, KRAS, HRAS, MEK, ERK, HER-2, HER-3, or MET. In one embodiment, the oncogene is KRAS.

In the embodiments described above, the methods of the present disclosure may be practiced in an assisted environment or a neo-assisted environment. The methods described herein may be expressed as first-line, second-line, third-line or more lines of treatment.

In some embodiments, the methods of the present disclosure may be represented as first-line therapy in individuals identified as having STK11 mutant cancer. In another embodiment, the methods of the present disclosure may be represented as second-line therapy in individuals identified as having cancer that is resistant to therapy (eg, resistance to chemotherapy, radiation, etc.). In one embodiment, standard therapies are ineffective, intolerable, or considered inappropriate for treating the patient's cancer.

This disclosure also provides methods of treating or preventing other cancer-related diseases, conditions or disorders. The terms cancer-related diseases, conditions and disorders are used broadly to refer to conditions directly or indirectly related to cancer and non-cancerous proliferative diseases, and include, for example, angiogenesis, precancerous conditions such as dysplasia and non-cancerous proliferative diseases. Disease conditions or disorders, such as benign proliferative breast disease and papillomas. For clarity, the term cancer-related diseases, conditions and disorders does not include cancer itself.

Generally, disclosed methods for treating or preventing cancer or cancer-related diseases, conditions, or disorders in an individual in need thereof comprise administering to the individual a compound disclosed herein. In some embodiments, the present disclosure provides methods of treating or preventing cancer or cancer-related diseases, conditions, or disorders using a compound disclosed herein and at least one additional therapy, examples of which are set forth elsewhere herein.

Viral infection. AXL has been found to promote infection by a variety of enveloped viruses, including, for example, coronaviruses, poxviruses, retroviruses, flaviviruses, arenaviruses, filoviruses and alphaviruses. In particular, enveloped viruses display phospholipid serine. The ligand of AXL, GAS6, connects the envelope phospholipid serine to the cell surface receptor AXL, thereby promoting the entry of enveloped viruses into cells. Especially for SARS-CoV-2, AXL is a co-receptor of ACE2, and the viral spike protein attaches to ACE2, allowing subsequent entry into host cells. In addition, AXL signaling inhibits virus-induced type I interferon (IFN) responses, leading to increased viral replication in infected cells and reduced antiviral defenses in neighboring cells. Therefore, inhibition of AXL is a useful strategy for treating viral infections.

In some embodiments, compounds according to the present disclosure can be used to treat viral infections. In some embodiments, the viral infection is caused by an enveloped virus. Exemplary viral infections include those caused by coronaviruses, poxviruses, retroviruses, flaviviruses, arenaviruses, filoviruses, or alphaviruses. In some embodiments, the viral infection is caused by a coronavirus (eg, MERS-CoV, SARS-CoV, SARS-CoV-2, 229E, NL63, OC43, or HKU1). In some embodiments, the viral infection is caused by a poxvirus (e.g., orthopoxvirus, parapoxvirus, mollusc poxvirus, astapox virus, capripox virus, swine pox virus, lepox virus, monkeypox virus, or avian pox virus). poxvirus). In some embodiments, the viral infection is caused by a retrovirus (e.g., human immunodeficiency virus (HIV), human T-lymphotropic virus type 1 (HTLV-1), or human T-lymphotropic virus type 2 (HTLV-II ))caused. In some embodiments, the viral infection is caused by a flavivirus (e.g., west nile, dengue, tick-borne encephalitis, yellow fever, Zika, swine fever, hepatitis C, or Japanese encephalitis). inflammation). In some embodiments, the viral infection is caused by an arenavirus (e.g., Chapare, Guanarito, Junin, Lassa, Machupo Macupo, Sabia, Whitewater Arroyo, or Lujo viruses. In some embodiments, the viral infection is caused by a filovirus (eg, Ebola, Marburg, Cueva, Dianlo, Stria, or Thamno virus). In some embodiments, the viral infection is caused by an alphavirus (e.g., Aura, Barmah Forest, Bebaru, Caaingua, Cabassou, Chikungunya virus, Eastern equine encephalitis virus, Eilat virus, Everglades virus, Fort Morgan virus, Getah virus, Highlands J, Madariaga, Mayaro, Middelburg, Mosso das Pedras, Mukan Mucambo, Ndumu, O'nyong'nyong, Pixuna, Rio Negro, Ross River virus Ross River), Salmon pancreas disease, Semliki Forest virus, Sindbis virus, Southern elephant seal virus, Tonate virus, Tero Caused by Trocara virus, Una virus, Venezuelan equine encephalitis virus, Western equine encephalitis virus or Whataroa virus.

In some embodiments, compounds according to the present disclosure can be used to treat infections caused by SARS-CoV-2, Ebola virus, monkeypox, or Zika virus. In some embodiments, compounds according to the present disclosure can be used to treat infections caused by SARS-CoV-2, Ebola virus, or Zika virus. In one embodiment, the infection is caused by SARS-CoV-2.

Fibrosis. AXL is expressed on fibroblasts and is related to the activation of myofibroblasts. Activated myofibroblasts are key effector cells associated with fibrosis in multiple organ systems. Therefore, inhibition of AXL is a promising anti-fibrotic treatment.

In some embodiments, compounds according to the present disclosure can be used to treat fibrosis. In some embodiments, the fibrosis is renal fibrosis (e.g., chronic kidney disease), intestinal fibrosis (e.g., Chron's disease), liver fibrosis, or pulmonary fibrosis (e.g., asthma or idiopathic pulmonary fibrosis (IPF)). In some embodiments, fibrosis is associated with cancer and tumor growth. In some embodiments, the fibrosis is tumor-associated tissue fibrosis. In some embodiments, tumor-associated tissue fibrosis is associated with pancreatic cancer.

In one embodiment, the compounds are useful in treating renal fibrosis. In some embodiments, renal fibrosis is associated with chronic kidney disease. In a further embodiment, the compounds may be used to treat renal fibrosis following unilateral ureteral obstruction (UUO). In one embodiment, renal fibrosis is associated with IgA nephropathy (ie, Berger's disease).

In some embodiments, the compounds are useful in treating intestinal fibrosis. In one embodiment, intestinal fibrosis is associated with Crohn's disease.

In some embodiments, the compounds are useful in treating liver fibrosis. In some embodiments, liver fibrosis is associated with chronic liver disease. In one embodiment, liver fibrosis is associated with non-alcoholic fatty liver disease (NAFLD).

In some embodiments, the compounds are useful in treating pulmonary fibrosis. In some embodiments, pulmonary fibrosis is associated with chronic lung disease. In further embodiments, the pulmonary fibrosis is idiopathic pulmonary fibrosis (IPF). In another embodiment, pulmonary fibrosis is associated with asthma.

pain. AXL is upregulated in injured dorsal root ganglia and is associated with neuropathic pain. Therefore, inhibition of AXL is a promising pain treatment strategy.

In one embodiment, compounds according to the present disclosure can be used to treat pain. In some embodiments, the pain is neuropathic pain.

Oncology patient selection. In some cases, methods according to the present disclosure may be provided in selected patients, e.g., identified as having, e.g., elevated AXL expression or AXL pathway activation in relevant tissues or samples, or having high microsatellite instability or Individuals with high tumor mutation burden. In some embodiments, patients are selected by assessing AXL expression (eg, soluble AXL (sAXL), cell surface AXL, or total AXL) in relevant tissues or samples. In some embodiments, patients are selected by assessing phospho-AXL levels. In some embodiments, patients are selected by assessing AXL genetic signature. In some embodiments, patients are selected by further assessment of GAS6 expression in relevant tissues or samples. In some embodiments, the present disclosure provides a method of treating cancer with a compound as described herein in a patient with elevated AXL expression, phospho-AXL levels, or AXL genetic signature. In one embodiment, the present disclosure provides a method of treating cancer in a patient with elevated cell surface expression of AXL using a compound as described herein. In another embodiment, the present disclosure provides a method of treating cancer in a patient with elevated expression of sAXL using a compound as described herein. In another embodiment, the present disclosure provides a method of treating cancer in a patient with elevated phospho-AXL levels using a compound as described herein. In another embodiment, the present disclosure provides a method of treating cancer in a patient with an elevated AXL gene signature using a compound as described herein. In yet another embodiment, the present disclosure provides a method of treating cancer in a patient with an elevated ratio of sAXL expression to GAS6 expression with a compound as described herein. In some embodiments, the present disclosure provides a method of administering a therapeutically effective amount of an AXL inhibitor to an individual to treat cancer based on determination of relative amounts of AXL expression. In another embodiment, the present disclosure provides a method of treating cancer by administering an effective amount of an AXL inhibitor to an individual based on determination of relative amounts of cell surface expression of AXL. In another embodiment, the present disclosure provides a method of treating cancer by administering an effective amount of an AXL inhibitor to an individual based on determination of relative amounts of sAXL expression or by complex AXL (cAXL) levels. In another embodiment, the present disclosure provides a method of administering an effective amount of an AXL inhibitor to an individual to treat cancer based on determination of relative amounts of phospho-AXL levels. In another embodiment, the present disclosure provides a method of administering an effective amount of an AXL inhibitor to an individual to treat cancer based on determination of the relative strength of the AXL gene signature. In yet another embodiment, the present disclosure provides a method of administering an effective amount of an AXL inhibitor to an individual to treat cancer based on determination of the relative amounts of the ratio of sAXL expression to GAS6 expression. In another embodiment, the present disclosure provides a method of administering to an individual an effective amount of an AXL inhibitor to treat cancer based on the presence of a STK11 mutation or deletion. In certain such embodiments, a suitable sample can be evaluated by performing LKB1 protein detection in the sample by sequencing such as next generation sequencing or by IHC in a suitable assay (e.g., Foundation I Liquid CDx) (e.g., blood or plasma) to identify such individuals. In some cases, individuals are identified as having oncogene-driven cancers that have mutations or overexpression of at least one cancer-related gene, such as ALK, ABL, AURORA, AKT, PDGFR, KIT, EGFR, VEGFR, FGFR3, FLT-3, MYC, RET, BRAF, PI3K, NF-κB, JAK, STAT, BCL-2, MCL-1, KRAS, HRAS, MEK, ERK, HER-2, HER-3, or MET. In some embodiments, an individual is identified as resistant to previous lines of treatment (eg, chemotherapy, radiation, etc.). Investment channels

In some embodiments, pharmaceutical compositions containing compounds according to the present disclosure can be in a form suitable for oral administration. Oral administration may involve swallowing the formulation, allowing the compound to be absorbed into the blood stream of the gastrointestinal tract. Alternatively, oral administration may involve buccal, lingual, or sublingual administration, allowing absorption of the compound into the bloodstream via the oral mucosa.

In another embodiment, pharmaceutical compositions containing compounds according to the present disclosure may be in a form suitable for parenteral administration. Forms of parenteral administration include, but are not limited to, intravenous, intraarterial, intramuscular, intradermal, intraperitoneal, intrathecal, intracisternal, intracerebral, intracerebroventricular, intraventricular, and subcutaneous. Pharmaceutical compositions suitable for parenteral administration may be formulated using suitable aqueous or non-aqueous carriers. Depot injections, typically administered subcutaneously or intramuscularly, may also be used to release the compounds disclosed herein over a defined period of time.

Other routes of administration are also contemplated by this disclosure, including but not limited to nasal, vaginal, intraocular, rectal, topical (eg, transdermal), and inhalation.

Specific embodiments of the present disclosure contemplate oral administration or parenteral administration. combination therapy

The present disclosure contemplates the use of an AXL inhibitor described herein alone or in combination with one or more additional therapies. Each additional therapy may be a therapeutic agent or another treatment modality. In embodiments that include one or more additional therapeutic agents, each agent may target a different but complementary mechanism of action. A compound of the present disclosure may have synergistic therapeutic or preventive effects on an underlying disease, condition or disorder when used in combination with one or more additional therapies. Additionally or alternatively, combination therapy may allow for dose reduction of one or more therapies, thereby ameliorating, reducing, or eliminating side effects associated with one or more agents.

In embodiments that include one or more additional therapeutic modalities, the AXL inhibitor can be administered before, after, or during treatment with the additional therapeutic modalities. In embodiments that include one or more additional therapeutic agents, the therapeutic agents used in such combination therapy may be formulated as a single composition or as separate compositions. If administered separately, each therapeutic agent in the combination can be administered at or about the same time or at different times. In addition, even if therapeutics are administered in different forms (e.g., oral capsules and intravenously), the therapeutics are administered in "combinations," with the therapeutics being administered at different dosing intervals during the patient's treatment, a The therapeutic agent is administered in a constant dosing regimen while the other therapeutic agent is increased titrated, decreased titrated, or interrupted, or each therapeutic agent in the combination is independently increased titrated, decreased titrated, increased or decreased dose, or interrupted and/or recovery. If the combination is formulated as separate compositions, in some embodiments, the separate compositions are provided together in a kit. cancer therapy

This disclosure contemplates the use of an AXL inhibitor described herein in combination with one or more additional therapies useful in the treatment of cancer.

In some embodiments, the one or more additional therapies are additional treatment modalities. Exemplary treatment modalities include, but are not limited to, surgical tumor resection, bone marrow transplantation, radiation therapy, and photodynamic therapy.

In some embodiments, the one or more additional therapies are therapeutic agents. Exemplary therapeutic agents include chemotherapeutic agents, radiopharmaceuticals, hormonal therapies, epigenetic modulators, ATP-adenosine axis targeting agents, targeted therapies, signal transduction inhibitors, RAS signaling inhibitors, PI3K inhibitors, sperm Aminase inhibitors, HIF inhibitors, PAK4 inhibitors, immunotherapeutics, cell therapy, gene therapy, immune checkpoint inhibitors, and agonists that stimulate or costimulate immune checkpoints. In one or more embodiments, the one or more additional therapies are selected from the group consisting of: inhibitors of the CD47-SIRPα pathway, tyrosine kinase inhibitors, inhibitors of HIF, inhibitors of PARP, RAS signaling inhibitors , immune checkpoint inhibitors, agents targeting extracellular production of adenosine, radiotherapy and chemotherapeutic agents.

In some embodiments, the one or more additional therapeutic agents are chemotherapeutic agents. Examples of chemotherapeutic agents include, but are not limited to, alkylating agents such as thiotepa and cyclophosphamide; alkyl sulfonates such as busulfan, improsulfan and piposil Piposulfan; aziridines, such as benzodopa, carboquone, meteredopa and uredopa; ethyleneimine and methylmelamine (methylamelamine), including altretamine, triethylmelamine, triethylphosphoramide, triethylphosphoramide and trimethylmelamine; nitrogen mustards, such as nitrogen mustard Chlorambucil, chlornaphazine, chlorambucil, estramustine, ifosfamide, mechlorethamine, dichloromethyldioxide Ethylamine hydrochloride, melphalan, novelbichin, phenesterine, prednimustine, trofosfamide, uracil mustard (uracil mustard); nitrosoureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine , ranimustine; antibiotics, such as aclacinomysin, actinomycin, authramycin, azoserine, bleomycin , actinomycin C (cactinomycin), calicheamicin (calicheamicin), carabicin (carabicin), caminomycin (caminomycin), carzinophilin (carzinophilin), chromomycins (chromomycins), actinomycin D (dactinomycin), daunorubicin, detorubicin, 6-diazo-5-side-oxy-L-norleucine, doxorubicin, epirubicin (epirubicin), esorubicin, idarubicin, marcellomycin, mitomycin, mycophenolic acid, nogalamycin ), olivomycin, pomalidomide, peplomycin, potfiromycin, puromycin, quelamycin, rhodo rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, lerubicin (zorubicin); antimetabolites, such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs, such as denopterin, methotrexate, and pteropterin , trimetrexate; purine analogs, such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogs, such as ancitabine ), azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, deoxyfluridine Doxifluridine, enocitabine, floxuridine, 5-FU; androgens such as calusterone, dromostanolone propionate, androstenol epitiostanol, mepitiostane, testolactone; anti-adrenergics such as aminoglutethimide, mitotane, trilostane; folic acid supplements, Such as folinic acid; aceglatone; aldophosphamide glycoside; aminoglycoside; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elformithine; elliptinium acetate); etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidamine; mitoguazone; mitoxantrone; mopidamol; nitracrine; penstatin; phenamet; pirarubicin; podophyllinic acid; 2-ethyl Procarbazine; razoxane; sizofiran; spirogermanium; tenuazonic acid; triaziquone; 2 ,2',2"-trichlorotriethylamine; urethan; vindesine; dacarbazine; mannomustine; mitobronitol; dibromomannitol Mitolactol; pipobroman; gacytosine; arabinoside ("Ara-C"); cyclophosphamide; thiotepa ; Paclitaxel, such as paclitaxel, nab paclitaxel and docetaxel; mechlorethamine; gemcitabine; 6-thioguanine; mercaptopurine; methylamine Pterin; platinum and platinum coordination complexes, such as cisplatin, carboplatin, and oxaliplatin; vinblastine; etoposide (VP-16) ; Ifosfamide; Mitomycin C; Mitoxantrone; Vincristine; Vinorelbine; Navelbine; Novantrone; Tenipal teniposide; daunomycin; aminopterin; xeloda; ibandronate; CPT11; proteasome inhibitors, such as bortezomib ), carfilzomib and ixazomib; topoisomerase inhibitors such as irinotecan, topotecan, etoposide, mitoxantrone, Teniposide; DMFO; retinoic acid; esperamicin; capecitabine; anthracycline and any of the above A pharmaceutically acceptable salt, acid or derivative of one. In certain embodiments, combination therapy includes a chemotherapy regimen including one or more chemotherapeutic agents. In one embodiment, combination therapy includes a chemotherapy regimen that includes one or more of: FOLFOX (leucovorin, fluorouracil, and oxaliplatin), FOLFIRI (e.g., leucovorin, fluorouracil, and irinotecan), Paclitaxel (eg, docetaxel, paclitaxel, nab-paclitaxel, etc.), low-dose cytarabine (LDAC), and/or gemcitabine. In one embodiment, combination therapy includes a chemotherapy regimen that includes one or more of: FOLFOX (leucovorin, fluorouracil, and oxaliplatin), FOLFIRI (e.g., leucovorin, fluorouracil, and irinotecan), Paclitaxel (e.g., docetaxel, paclitaxel, nab-paclitaxel, etc.), low-dose cytarabine (LDAC), gemcitabine, and/or platinum-based therapies (e.g., cisplatin, carboplatin, and oxalidine platinum).

In some embodiments, the one or more additional therapeutic agents are radiopharmaceuticals. Radiopharmaceuticals are a form of internal radiation therapy in which a radioactive source (ie, one or more radionuclides) is placed into an individual's body. Radioactive sources can be in solid or liquid form. Non-limiting examples of radiopharmaceuticals include sodium iodide 1-131, radium-223 dichloride, benzene iodine-131, radioiodinated vesicles (e.g., sphingolipid-activated protein C-dioleyl phosphatidylserine (SapC-DOPS nanovesicles), various forms of brachytherapy, and various forms of targeted radionuclides. Targeted radionuclides include radionuclides bound (e.g., through covalent or ionic interactions) to molecules ("targeting agents") that specifically bind to targets on cells, typically cancer cells or immune cells . Targeting agents can be small molecules, carbohydrates (including oligosaccharides and polysaccharides), antibodies, lipids, proteins, peptides, non-natural polymers or aptamers. In some embodiments, the targeting agent is a carbohydrate (including oligosaccharide and polysaccharide), lipid, protein or peptide, and the target is a tumor-associated antigen (enriched but not specific for cancer cells), a tumor-specific antigen (in normal Little to no expression in tissues) or neoantigens (cancer cell genome-specific antigens produced by non-synonymous mutations in the tumor cell genome). In some embodiments, the targeting agent is an antibody and the target is a tumor-associated antigen (i.e., an antigen that is enriched but not specific for cancer cells), a tumor-specific antigen (i.e., an antigen that has little to no expression in normal tissue) ) or neoantigens (that is, cancer cell genome-specific antigens produced by non-synonymous mutations in the tumor cell genome). Non-limiting examples of targeted radionuclides include radionuclides attached to somatostatin or its peptide analogs (e.g., 177Lu-Dotatate, etc.); prostate-specific membrane antigen or its peptide analogs (e.g., 177Lu -PSMA-617, 225Ac-PSMA-617, 177Lu-PSMA-I&T, 177Lu-MIP-1095, etc.); homologous ligands of the receptor, peptides derived from the ligands, or variants thereof (e.g., 188Re-labeled VEGF _125-136 or its variants with higher affinity for VEGF receptors, etc.); antibodies targeting tumor antigens (for example, 131I-tositumomab (tositumomab), 90Y-ibritumomab (ibritumomab tiuxetan) ), CAM-H2-I131 (Precirix NV), I131-omburtamab (omburtamab), etc.).

In some embodiments, the one or more additional therapeutic agents are hormone therapy. Hormone therapy is used to regulate or inhibit the effects of hormones on tumors. Examples of hormonal therapies include, but are not limited to: selective estrogen receptor degraders such as fulvestrant, giredestrant, SAR439859, RG6171, AZD9833, rintodestrant , ZN-c5, LSZ102, D-0502, LY3484356, SHR9549; selective estrogen receptor modulators, such as tamoxifen, raloxifene, 4-hydroxytamoxifen, and tamoxifen , Keoxifene, toremifene; aromatase inhibitors, such as anastrozole, exemestane, letrozole and others that inhibit aromatase 4 (5)-imidazole; gonadotropin-releasing hormone agonists, such as nafarelin, triptorelin, goserelin; gonadotropin-releasing hormone antagonists, such as di degarelix; antiandrogens such as abiraterone, enzalutamide, apalutamide, darolutamide, flutamide, nilutamide, bicalutamide, leuprolide; 5α-reductase inhibitors such as finasteride, dutasteride; and the like . In certain embodiments, combination therapy includes administration of a hormone or related hormonal agent. In one embodiment, the combination therapy includes administration of enzalutamide.

In some embodiments, the one or more additional therapeutic agents are epigenetic modulators. Epigenetic modulators alter the epigenetic mechanisms that control gene expression and can be, for example, inhibitors or activators of epigenetic enzymes. Non-limiting examples of epigenetic modulators include DNA methyltransferase (DNMT) inhibitors, hypomethylating agents, and histone deacetylase (HDAC) inhibitors. In one or more embodiments, an AXL inhibitor according to the present disclosure is combined with a DNA methyltransferase (DNMT) inhibitor or hypomethylating agent. Exemplary DNMT inhibitors include decitabine, zebularine, and azacitidine. In one or more embodiments, combinations of compounds according to the present disclosure with histone deacetylase (HDAC) inhibitors are also contemplated. Exemplary HDAC inhibitors include vorinostat, givinostat, abexinostat, panobinostat, belinostat, and trichostatin A (trichostatin A).

In some embodiments, the one or more additional therapeutic agents are ATP-adenosine axis targeting agents. ATP-adenosine axis targeting agents alter signaling mediated by adenosine nucleosides and nucleotides (e.g., adenosine, AMP, ADP, ATP), for example, by modulating adenosine levels or targeting adenosine receptors. Adenosine and ATP, which act on different types of receptors, often have opposite effects on inflammation, cell proliferation, and cell death. For example, ATP and other adenine nucleotides have anti-tumor effects through activation of the PS2Y1 receptor subtype, and the accumulation of adenosine in the tumor microenvironment has been shown to inhibit the anti-tumor functions of various immune cells and by interacting with the cell surface. Adenosine receptor binding enhances the immunosuppressive activity of myeloid and regulatory T cells. In certain embodiments, the ATP-adenosine axis-targeting agent is an inhibitor of an exonucleotidase involved in the conversion of ATP to adenosine or an antagonist of an adenosine receptor. Nucleotidase enzymes involved in converting ATP to adenosine include exonucleoside triphosphate diphosphate hydrolase 1 (ENTPD1, also known as CD39 or cluster of differentiation 39) and exonucleoside 5'-nucleotidase (NT5E or 5NT , also known as CD73 or cluster of differentiation 73). Exemplary small molecule CD73 inhibitors include CB-708, ORIC-533, LY3475070, and quemliclustat (AB680). Exemplary anti-CD39 and anti-CD73 antibodies include ES002023, TTX-030, IPH-5201, SRF-617, CPI-006, oleclumab (MEDI9447), NZV930, IPH5301, GS-1423, Ureli Monoclonal antibodies (uliledlimab) (TJD5, TJ004309), AB598 and BMS-986179. In one embodiment, the present disclosure contemplates combinations of AXL inhibitors and CD73 inhibitors described herein, such as those described in WO 2017/120508, WO 2018/067424, WO 2018/094148, and WO 2020/046813. In a further embodiment, the CD73 inhibitor is Quinlistat. Adenosine binds to and activates four different G protein-coupled receptors: A ₁ R, A _2A R, A _2B R, and A ₃ R. A ₂ R antagonists include etrumadenant, inupadenant, taminadenant, caffeine citrate, NUV-1182, TT-702, DZD-2269, INCB-106385 , EVOEXS-21546, AZD-4635, imaradenant, RVU-330, ciforadenant, PBF-509, PBF-999, PBF-1129 and CS-3005. In some embodiments, the present disclosure contemplates combinations of an AXL inhibitor described herein with an A2 _AR antagonist, an A2 _BR antagonist, or an antagonist of both _A2 AR and A2 _BR . In some embodiments, the present disclosure contemplates combinations of compounds described herein with adenosine receptor antagonists described in WO 2018/136700, WO 2018/204661, WO 2018/213377, or WO 2020/023846. In one embodiment, the adenosine receptor antagonist is elumelon.

In some embodiments, the one or more additional therapeutic agents are targeted therapies. In one aspect, targeted therapy may include a chemotherapeutic agent, a radionuclide, a hormonal therapy, or another small molecule drug linked to the targeting agent. Targeting agents can be small molecules, carbohydrates (including oligosaccharides and polysaccharides), antibodies, lipids, proteins, peptides, non-natural polymers or aptamers. In some embodiments, the targeting agent is a carbohydrate (including oligosaccharide and polysaccharide), lipid, protein or peptide, and the target is a tumor-associated antigen (enriched but not specific for cancer cells), a tumor-specific antigen (in normal Little to no expression in tissues) or neoantigens (cancer cell genome-specific antigens produced by non-synonymous mutations in the tumor cell genome). In some embodiments, the targeting agent is an antibody and the target is a tumor-associated antigen (enriched but not specific for cancer cells), a tumor-specific antigen (little to no expression in normal tissue), or a neoantigen (generated by tumor cells) Cancer cell genome-specific antigens produced by non-synonymous mutations in the genome). Specific examples include, but are not limited to, patritumab deruxtecan and telisotuzumab vedotin. In other forms, targeted therapies inhibit or interfere with specific proteins that help tumors grow and/or spread. Non-limiting examples of such targeted therapies include signaling inhibitors, RAS signaling inhibitors, oncogenic transcription factor inhibitors, oncogenic transcription factor repressor activators, angiogenesis inhibitors, immunotherapeutics, tyrosine kinase inhibition Agents, ATP-adenosine axis targeting agents, PARP inhibitors, PAK4 inhibitors, PI3K inhibitors, HIF-2α inhibitors, CD39 inhibitors, CD73 inhibitors, A2R antagonists, TIGIT antagonists and PD-1 antagonists . ATP-adenosine axis targeting agents are described above, while other agents are described in further detail below.

In some embodiments, the one or more additional therapeutic agents are signaling inhibitors. Signal transduction inhibitors are agents that selectively inhibit one or more steps in the signaling pathway. Signal transduction inhibitors (STIs) contemplated by this disclosure include, but are not limited to: (i) BCR-ABL kinase inhibitors (e.g., imatinib); (ii) epidermal growth factor receptor tyrosine kinase Inhibitors (EGFR TKIs), including small molecule inhibitors (e.g., CLN-081, gefitinib, erlotinib, afatinib, icotinib) and osimertinib) and anti-EGFR antibodies; (iii) inhibitors of the human epidermal growth factor (HER) family of transmembrane tyrosine kinases, such as HER-2/neu receptor inhibitors (e.g., tocilizumab (trastuzumab) and HER-3 receptor inhibitors; (iv) vascular endothelial growth factor receptor (VEGFR) inhibitors, including small molecule inhibitors (e.g., axitinib, sunil sunitinib and sorafenib), VEGF kinase inhibitors (e.g., lenvatinib, cabozantinib, pazopanib, tivozanib (tivozanib, XL092, etc.) and anti-VEGF antibodies (e.g., bevacizumab); (v) inhibitors of AKT family kinases or AKT pathways (e.g., rapamycin); (vi) Inhibitors of serine/threonine protein kinase B-Raf (BRAF), such as vemurafenib, dabrafenib and encorafenib; (vii) Re-transfection (RET) inhibitors, including, for example, selpercatinib and pralsetinib; (viii) Tyrosine protein kinase Met (c-MET) inhibitors (e.g., terpotinib (tepotinib, tivantinib, cabozantinib, and crizotinib); (ix) polymorphic lymphoma kinase (ALK) inhibitors (e.g., ensartinib ensartinib), ceritinib (ceritinib), lorlatinib (lorlatinib), crizotinib (crizotinib) and brigatinib (brigatinib)); (x) inhibitors of the RAS signaling pathway as described elsewhere herein (For example, inhibitors of KRAS, HRAS, RAF, MEK, ERK); (xi) FLT-3 inhibitors (for example, gilteritinib); (xii) Trop-2 inhibitors, such as antibody drugs Conjugate sacituzumab govitecan-hziy (sacituzumab govitecan-hziy); (xiii) Inhibitors of the JAK/STAT pathway, such as JAK inhibitors (including tofacitinib and luliti (ruxolitinib) or STAT inhibitors (such as napabucasin); (xiv) inhibitors of NF-κB; (xv) cell cycle kinase inhibitors (e.g., flavopiridol); ( xvi) Phosphatidyl inositol kinase (PI3K) inhibitors; (xix) Protein kinase B (AKT) inhibitors (e.g., capivasertib, miransertib); (xx) Platelet-derived growth PDGFR inhibitors (e.g., imatinib, sunitinib, regorafenib, avapritinib, lenvatinib, nintedanib, Famitinib, ponatinib, axitinib, repretinib, etc.); and (xxi) Insulin-like growth factor receptor (IGFR) inhibitors (e.g., Erlot afatinib, gefitinib, osimertinib, dacomitinib). In one or more embodiments, additional therapeutic agents include inhibitors of EGFR, VEGFR, PDGFR, IGFR, HER-2, HER-3, BRAF, RET, MET, ALK, RAS (e.g., KRAS, MEK, ERK), FLT-3, JAK, STAT, NF-κB, PI3K and/or AKT or any combination thereof. In one embodiment, the additional therapeutic agent includes a tyrosine kinase inhibitor that inhibits one or more of: EGFR, VEGFR, HER-2, HER-3, BRAF, PDGFR, c-MET, MEK, ERK, ALK, RET, KIT, IGFR, TRK and/or FGFR. In some embodiments, additional therapeutic agents include tyrosine kinase inhibitors that inhibit one or more of: EGFR, VEGFR, and/or c-MET.

In some embodiments, the one or more additional therapeutic agents are agents that prevent, inhibit, or slow autophagy. Autophagy is increased in various tumor environments and drives downregulation of major histocompatibility complex class I molecules (MHC-I) and related antigen presentation machinery. Downregulation of antigen presentation reduces the sensitivity of cancer cells to T cell-mediated killing. One strategy to prevent, inhibit, or slow down autophagy is to target Unc-51-like autophagy-activating kinase 1/2 (ULK1 and/or ULK2). Exemplary inhibitors of ULK1 and/or ULK2 include DC-3116, ERAS-5 and ENV-201. In some embodiments, the one or more additional therapeutic agents are inhibitors of ULK1, ULK2, or both ULK1 and ULK2.

In some embodiments, the one or more additional therapeutic agents are RAS signaling inhibitors. Oncogenic mutations in the RAS gene family (eg, HRAS, KRAS, and NRAS) are associated with a variety of cancers. For example, mutations in G12C, G12D, G12V, G12A, G13D, Q61H, G13C, and G12S in the KRAS gene family have been observed in various tumor types. Direct and indirect inhibition strategies have been investigated for inhibiting mutant RAS signaling. Indirect inhibitors target effectors other than RAS in the RAS signaling pathway, including but not limited to inhibitors of RAF, MEK, ERK, PI3K, PTEN, SOS (e.g., SOS1), mTORC1, SHP2 (PTPN11), and AKT. Non-limiting examples of indirect inhibitors under development include RMC-4630, RMC-5845, RMC-6291, RMC-6236, JAB-3068, JAB-3312, TNO155, RLY-1971, BI1701963, everolimus ). Direct inhibitors of RAS mutants have also been explored and typically target the KRAS-GTP complex or the KRAS-GDP complex. Exemplary direct RAS inhibitors in development include, but are not limited to, sotorasib (AMG510), adagrasib (MRTX849), mRNA-5671 and ARS1620. In some embodiments, the one or more RAS signaling inhibitors are selected from the group consisting of: RAF inhibitor, MEK inhibitor, ERK inhibitor, PI3K inhibitor, PTEN inhibitor, SOS1 inhibitor, mTORC1 inhibitor, SHP2 inhibitor agents and AKT inhibitors. In other embodiments, one or more inhibitors of RAS signaling directly inhibit RAS mutants.

In some embodiments, the one or more additional therapeutic agents are inhibitors of phosphoinositide 3-kinase (PI3K), particularly inhibitors of PI3Kγ and/or PI3Kδ isoforms. PI3Kγ inhibitors can stimulate anti-cancer immune responses by modulating myeloid cells, such as by inhibiting suppressive myeloid cells, suppressing immunosuppressive tumor-infiltrating macrophages, or by stimulating the production of macrophages and dendritic cells that contribute to Effective T cell response to interleukins thereby reducing the development and spread of cancer. Exemplary PI3Kγ inhibitors include copanlisib, duvelisib, AT-104, ZX-101, tenalisib, eganelisib, SF-1126, AZD3458 and pictilisib. In some embodiments, an AXL inhibitor according to the present disclosure is combined with one or more PI3Kγ inhibitors described in WO 2020/0247496A1. In addition, PI3Kδ is expressed on malignant B cells and plays a role in promoting B cell activation, differentiation, proliferation and survival. Exemplary PI3Kδ inhibitors include duvicoxib, leniolisib, idelalisib, parsaclisib, cobancoxib, umbralisib, Zandex zandelisib, egaliseb, linperlisib, pilaralisib and tenalisib,

In some embodiments, the one or more additional therapeutic agents are inhibitors of arginase. Arginase has been shown to be responsible for or involved in inflammation-induced immune dysfunction, tumor immune escape, immunosuppression, and the immunopathology of infectious diseases. Exemplary arginase compounds include CB-1158 and OAT-1746. In some embodiments, an AXL inhibitor according to the present disclosure is combined with one or more arginase inhibitors described in WO/2019/173188 and WO 2020/102646.

In some embodiments, the one or more additional therapeutic agents are inhibitors of oncogenic transcription factors or activators of oncogenic transcription factor repressors. Suitable agents may act at the expression level (eg, RNAi, siRNA, etc.), via physical degradation, at the protein/protein level, at the protein/DNA level, or by binding in the activation/inhibition pocket. Non-limiting examples include inhibitors of one or more subunits of the MLL complex (e.g., HDAC, DOT1L, BRD4, Menin, LEDGF, WDR5, KDM4C (JMJD2C), and PRMT1), hypoxia-inducible factor (HIF) transcription factors inhibitors and the like.

In some embodiments, the one or more additional therapeutic agents are inhibitors of hypoxia-inducible factor (HIF) transcription factors, particularly HIF-2α. Exemplary HIF-2α inhibitors include belzutifan, ARO-HIF2, PT-2385, and those described in WO 2021113436 and WO 2021188769. In some embodiments, compounds according to the present disclosure are combined with one or more HIF-2α inhibitors described in WO 2021188769. In one embodiment, the HIF-2α inhibitor is AB521.

In some embodiments, the one or more additional therapeutic agents are inhibitors of p21-activated kinase 4 (PAK4). PAK4 overexpression has been demonstrated in multiple cancer types, including cancers that are resistant to PD-1 therapy. Although no PAK4 inhibitors have yet been approved, some are in development and exhibit dual PAK4/NAMPT inhibitor activity, such as ATG-019 and KPT-9274. In some embodiments, compounds according to the present disclosure are combined with PAK4-selective inhibitors. In some embodiments, compounds according to the present disclosure are combined with dual PAK4/NAMPT inhibitors such as ATG-019 or KPT-9274.

In some embodiments, the one or more additional therapeutic agents are (i) agents that inhibit the enzyme poly(ADP-ribose) polymerase (e.g., olaparib, niraparib, and lucap (rucaparib, etc.); (ii) inhibitors of the Bcl-2 protein family (for example, venetoclax, navitoclax, etc.); (iii) inhibitors of MCL-1; ( iv) Inhibitors of the CD47-SIRPα pathway (e.g., anti-CD47 antibodies, magrolimab, etc.); (v) Isocitrate dehydrogenase (IDH) inhibitors, such as IDH-1 or IDH-2 inhibition agents (e.g., ivosidenib, enasidenib, etc.).

In some embodiments, the one or more additional therapeutic agents are immunotherapeutic agents. Immunotherapeutic agents treat disease by stimulating or suppressing the immune system. Immunotherapeutic agents that can be used to treat cancer often trigger or enhance an immune response against cancer cells. Non-limiting examples of suitable immunotherapeutic agents include: immunomodulators; cellular immunotherapies; vaccines; gene therapies; ATP-adenosine axis targeting agents; immune checkpoint modulators; and certain signal transduction inhibitors. ATP-adenosine axis targeting agents and signal transduction inhibitors are as described above. Immunomodulators, cellular immunotherapies, vaccines, gene therapies, and immune checkpoint modulators are further described below.

In some embodiments, the one or more additional therapeutic agents are immunotherapeutic agents, more specifically interleukins or chemokines, such as IL-1, IL-2, IL-12, IL-18, ELC/CCL19, SLC/CCL21, MCP-1, IL-4, TNF, IL-15, MDC, IFNa/b, M-CSF, IL-3, GM-CSF, IL-13 and anti-IL-10; bacterial lipopolysaccharide (LPS ); organic or inorganic adjuvants that activate antigen-presenting cells and promote the presentation of antigen epitopes on major histocompatibility complex molecule agonists include, but are not limited to, Toll-like receptor (TLR) agonists, mevalonate Pathway antagonists, STING agonists; indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors and immunostimulatory oligonucleotides, and other T cell adjuvants.

In some embodiments, the one or more additional therapeutic agents are immunotherapeutic agents, more specifically cell therapy. Cell therapy is a form of treatment in which living cells are administered to an individual. In certain embodiments, the one or more additional therapeutic agents are cellular immunotherapy that activates or suppresses the immune system. Cellular immunotherapies used to treat cancer often trigger or enhance immune responses. The cells can be autologous or allogeneic immune cells (eg, monocytes, macrophages, dendritic cells, NK cells, T cells, etc.) collected from one or more individuals. Alternatively, the cells may be "(re)programmed" allogeneic immune cells generated from immune precursor cells (e.g., lymphoid progenitor cells, myeloid progenitor cells, common dendritic cell precursor cells, stem cells, induced pluripotent stem cells, etc.). In some embodiments, such cells can be an expanded subset of cells with distinct effector functions and/or maturation markers (e.g., adaptive memory NK cells, tumor-infiltrating lymphocytes, immature dendritic cells, monocytes, sphere-derived dendritic cells, plasmacytoid dendritic cells, conventional dendritic cells (sometimes called classical dendritic cells), M1 macrophages, M2 macrophages, etc.), which can be genetically modified to target cells Anti-tumor effects of specific antigens and/or enhanced cells (e.g., engineered T cell receptor (TCR) cell therapy, chimeric antigen receptor (CAR) cell therapy, lymph node homing of antigen-loaded dendritic cells, etc.), Can be designed to express or increase the expression of tumor-associated antigens, or can be any combination thereof. Non-limiting types of cell therapy include CAR-T cell therapy, CAR-NK cell therapy, TCR therapy and dendritic cell vaccines. Exemplary cellular immunotherapies include sipuleucel-T, tisagenlecleucel, lisocabtagene maraleucel, idecabtagene vicleucel, brexucabtagene autoleucel) and axicabtagene ciloleucel, as well as CTX110, JCAR015, JCAR017, MB-CART19.1, MB-CART20.1, MB-CART2019.1, UniCAR02-T-CD123, BMCA-CAR-T, JNJ -68284528, BNT211 and NK-92/5.28.z.

In some embodiments, the one or more additional therapeutic agents are immunotherapeutic agents, more specifically gene therapy. Gene therapy involves the ex vivo administration of recombinant nucleic acids to an individual or individual cells to modify the expression of endogenous genes or to cause heterologous expression of proteins (e.g., small interfering RNA (siRNA) agents, double-stranded RNA (dsRNA) agents, microRNA RNA (miRNA) agents, viral or bacterial gene delivery, etc.), and genes that may or may not contain nucleic acid components (e.g., meganucleases, zinc finger nucleases, TAL nucleases, CRISPR/Cas nucleases, etc.) Editing therapies, oncolytic viruses and the like. Non-limiting examples of gene therapies useful in cancer treatment include Gendicine® (rAd-p53), Oncorine® (rAD5-H101), talimogene laherparepvec, Mx-dnG1, ARO-HIF2 (Arrowhead), quaratusugene ozeplasmid (Immunogene), CTX110 (CRISPR Therapeutics), CTX120 (CRISPR Therapeutics) and CTX130 (CRISPR Therapeutics).

In some embodiments, the one or more additional therapeutic agents are immunotherapeutic agents, more specifically agents that modulate immune checkpoints. Immune checkpoints are a set of inhibitory and stimulatory pathways that directly affect the function of immune cells (eg, B cells, T cells, NK cells, etc.). Immune checkpoints are involved when proteins on the surface of immune cells recognize and bind to their cognate ligands. The present invention contemplates the use of an AXL inhibitor described herein in combination with agonists that stimulate or costimulatory pathways and/or antagonists that inhibit pathways. Agonists of stimulatory or costimulatory pathways and antagonists of inhibitory pathways can be used to overcome different immunosuppressive pathways in the tumor microenvironment, inhibit T regulatory cells, reverse/prevent T cell unresponsiveness or exhaustion, trigger innate immune activation, and/or Inflammation at the tumor site or a combination thereof.

In some embodiments, the one or more additional therapeutic agents are immune checkpoint inhibitors. As used herein, the term "immune checkpoint inhibitor" refers to an antagonist of an inhibitory or co-inhibitory immune checkpoint. The terms "immune checkpoint inhibitor," "checkpoint inhibitor," and "CPI" are used interchangeably herein. Immune checkpoint inhibitors can antagonize inhibitory or co-suppressive immune checkpoints by interfering with receptor-ligand binding and/or altering receptor signaling. Examples of immune checkpoints (ligands and receptors), some of which are selectively upregulated in various types of cancer cells and can be antagonized, include PD-1 (programmed cell death protein 1); PD-L1 (PD1 ligand body); BTLA (B and T lymphocyte attenuator); CTLA-4 (cytotoxic T lymphocyte-associated antigen 4); TIM-3 (T cell immunoglobulin and mucin domain-containing protein 3); LAG-3 (lymphocyte activation gene 3); TIGIT (T cell immune receptor with Ig and ITIM domains); CD276 (B7-H3), PD-L2, galectin 9, CEACAM-1, CD69, galectin -1. CD113, GPR56, VISTA, 2B4, CD48, GARP, PD1H, LAIR1, TIM-1 and TIM-4, as well as killer inhibitory receptors, can be divided into two categories according to their structural characteristics: i) Killer cell immunoglobulin like receptors (KIR), and ii) C-type lectin receptors (members of the type II transmembrane receptor family). Other less well-defined immune checkpoints described in the literature were also considered, including receptors (e.g., the 2B4 (also known as CD244) receptor) and ligands (e.g., certain B7 family inhibitory ligands such as B7- H3 (also known as CD276) and B7-H4 (also known as B7-S1, B7x, and VCTN1)). [See Pardoll, (April 2012) Nature Rev. Cancer 12:252-64].

In some embodiments, the immune checkpoint inhibitor is a CTLA-4 antagonist. In further embodiments, the CTLA-4 antagonist can be an antagonist CTLA-4 antibody. Suitable antagonist CTLA-4 antibodies include, for example, monospecific antibodies such as ipilimumab or tremelimumab, and bispecific antibodies such as MEDI5752 and KN046.

In some embodiments, the immune checkpoint inhibitor is a PD-1 antagonist. In further embodiments, the PD-1 antagonist can be an antagonist PD-1 antibody, small molecule or peptide. Suitable antagonist PD-1 antibodies include, for example, monospecific antibodies such as balstilimab, budigalimab, camrelizumab, cosibelimab ), dostarlimab, cemiplimab, ezabenlimab (BI-754091), MEDI-0680 (AMP-514; WO2012/145493), nivolumab nivolumab, pembrolizumab, pidilizumab (CT-011), pimivalimab, retifanlimab, sarsanide sasanlimab, spartalizumab, sintilimab, tislelizumab, toripalimab and sepalizumab (zimberelimab); and bispecific antibodies such as LY3434172. In a further embodiment, the PD-1 antagonist may be a recombinant protein consisting of the extracellular domain of PD-L2 (B7-DC) fused to the Fc portion of IgGl (AMP-224). In certain embodiments, the immune checkpoint inhibitor is cepalizumab.

In some embodiments, the immune checkpoint inhibitor is a PD-L1 antagonist. In further embodiments, the PD-L1 antagonist can be an antagonist PD-L1 antibody. Suitable antagonist PD-L1 antibodies include, for example, monospecific antibodies such as avelumab, atezolizumab, durvalumab, BMS-936559, and envolizumab. anti-(envafolimab), and bispecific antibodies such as LY3434172 and KN046.

In some embodiments, the immune checkpoint inhibitor is a TIGIT antagonist. In further embodiments, the TIGIT antagonist can be an antagonist TIGIT antibody. Suitable antagonist anti-TIGIT antibodies include monospecific antibodies such as AGEN1327, AB308 (WO2021247591), BMS 986207, COM902, domvanalimab, EOS-448, etigilimab, IBI-929 , JS006, M6223, ociperlimab, SEA-TGT, tiragolumab, vibostolimab; and bispecific antibodies such as AGEN1777 and AZD2936. In certain embodiments, the immune checkpoint inhibitor is an antagonist anti-TIGIT antibody disclosed in WO2017152088 or WO2021247591. In certain embodiments, the immune checkpoint inhibitor is dofenumab or AB308.

In some embodiments, the immune checkpoint inhibitor is a LAG-3 antagonist. In further embodiments, the LAG-3 antagonist can be an antagonist LAG-3 antibody. Suitable antagonist LAG-3 antibodies include, for example, BMS-986016 (WO10/19570, WO14/08218) or IMP-731 or IMP-321 (WO08/132601, WO09/44273).

In certain embodiments, the immune checkpoint inhibitor is a B7-H3 antagonist. In a further embodiment, the B7-H3 antagonist is an antagonist B7-H3 antibody. Suitable antagonist B7-H3 antibodies include, for example, enoblituzumab (MGA271; WO11/109400), obituzumab, DS-7300a, ABBV-155 and SHR-A1811.

In some embodiments, one or more additional therapeutic agents activate stimulatory or costimulatory immune checkpoints. Examples of stimulatory or costimulatory immune checkpoints (ligands and receptors) include B7-1, B7-2, CD28, 4-1BB (CD137), 4-1BBL, ICOS, ICOS-L, OX40, OX40L, GITR, GITRL, CD70, CD27, CD40, DR3 and CD2.

In some embodiments, the agent that activates a stimulatory or costimulatory immune checkpoint is a CD137 (4-1BB) agonist. In further embodiments, the CD137 agonist can be a agonist CD137 antibody. Suitable CD137 antibodies include, for example, urelumab and utomilumab (PF-05082566; WO12/32433). In some embodiments, the agent that activates a stimulatory or costimulatory immune checkpoint is a GITR agonist. In further embodiments, the GITR agonist may be a agonist GITR antibody. Suitable GITR antibodies include, for example, BMS-986153, BMS-986156, TRX-518 (WO06/105021, WO09/009116) and MK-4166 (WO11/028683). In some embodiments, the agent that activates a stimulatory or costimulatory immune checkpoint is an OX40 agonist. In further embodiments, the OX40 agonist can be a agonist OX40 antibody. Suitable OX40 antibodies include, for example, MEDI-6383, MEDI-6469, MEDI-0562, PF-04518600, GSK3174998, BMS-986178, and MOXR0916. In some embodiments, the agent that activates a stimulatory or costimulatory immune checkpoint is a CD40 agonist. In further embodiments, the CD40 agonist can be a agonist CD40 antibody. In some embodiments, the agent that activates a stimulatory or costimulatory immune checkpoint is a CD27 agonist. In further embodiments, the CD27 agonist can be a agonist CD27 antibody. Suitable CD27 antibodies include, for example, varlilumab.

In some embodiments, the one or more additional therapeutic agents are agents that suppress or deplete immunosuppressive immune cells. For example, to inhibit or eliminate immunosuppressive macrophages or monocytes, the agent can be a CSF-1R antagonist, such as a CSF-1R antagonist antibody, including RG7155 (WO11/70024, WO11/107553, WO11/131407, WO13/87699, WO13/119716, WO13/132044) or FPA-008 (WO11/140249; WO13169264). As another example WO14/036357). Ex vivo anti-CD25 bead depletion of Tregs.

In some embodiments, each additional therapeutic agent can independently be a chemotherapeutic agent, radiopharmaceutical, hormonal therapy, epigenetic modulator, targeting agent, immunotherapeutic agent, cell therapy, or gene therapy. For example, in one embodiment, the present disclosure encompasses the use of an AXL inhibitor described herein in combination with one or more chemotherapeutic agents and, optionally, one or more additional therapeutic agents, wherein each additional therapeutic agent is independently radioactive. Drugs, hormone therapies, targeted agents, immunotherapeutic agents, cell therapies or gene therapies. In another embodiment, the present disclosure contemplates the use of an AXL inhibitor described herein in combination with one or more chemotherapeutic agents and, optionally, one or more additional therapeutic agents, wherein each additional therapeutic agent is independently targeted agents, immunotherapeutics or cell therapies. In another embodiment, the present disclosure encompasses the use of an AXL inhibitor described herein in combination with one or more immunotherapeutic agents and optionally one or more additional therapeutic agents, wherein each additional therapeutic agent is independently a radiopharmaceutical , hormone therapy, targeted agents, chemotherapeutic agents, cell therapy or gene therapy. In another embodiment, the present disclosure encompasses the use of an AXL inhibitor described herein in combination with one or more immunotherapeutic agents and, optionally, one or more additional therapeutic agents, wherein each additional therapeutic agent is independently chemotherapy agents, targeted agents or cell therapies. In another embodiment, the present disclosure encompasses an AXL inhibitor described herein with one or more immune checkpoint inhibitors and/or one or more ATP-adenosine axis targeting agents and optionally one or more additional Use of a combination of therapeutic agents, wherein each additional therapeutic agent is independently a chemotherapeutic agent, a targeted agent, an immunotherapeutic agent, or a cell therapy. In further embodiments of (a) above, the targeting agent may be a PI3K inhibitor, an arginase inhibitor, a HIF2α inhibitor, an inhibitor of the CD47-SIRPα pathway, a tyrosine kinase inhibitor, a PARP inhibitor, or PAK4 inhibitors; (b) Tyrosine kinase inhibitors can inhibit one or more of the following: EGFR, VEGF, HER-2, HER-3, BRAF, PDGFR, MET, MEK, ERK, ALK, RET, KIT , IGFR, TRK and/or FGFR; (c) Tyrosine kinase inhibitors can inhibit one or more of the following: EGFR, VEGFR and/or c-MET; (d) Immunotherapeutic agents are ATP-adenosine axis Targeting agents or immune checkpoint inhibitors; (e) ATP-adenosine axis targeting agents are A2 _A R and/or A2 _BR antagonists, CD73 inhibitors or CD39 inhibitors; (f) ATP-adenosine axis The targeting agent is elumelon, quinlistat or AB598; (g) the immunotherapy agent is anti-PD-1 antagonist antibody or anti-TIGIT antagonist antibody; (h) the immunotherapy agent is cepalizumab ( zimberelimab), dofenumab or AB308; or (i) any combination thereof. In further embodiments of the above, the present disclosure contemplates an AXL inhibitor described herein in combination with dofenumab, elumelan, quinlistat, cepalizumab, AB308, AB598, AB521, or any of The use of combinations of combinations.

In one or more embodiments, the one or more additional therapies are selected from the group consisting of: inhibitors of the CD47-SIRPα pathway, tyrosine kinase inhibitors, inhibitors of HIF, inhibitors of PARP, RAS signaling inhibitors , immune checkpoint inhibitors, agents targeting extracellular production of adenosine, radiotherapy and chemotherapeutic agents. In some embodiments, the inhibitor of the CD47-SIRPα pathway is an anti-CD47 antibody. In some embodiments, the tyrosine kinase inhibitor inhibits one or more of: EGFR, VEGF, HER-2, HER-3, BRAF, PDGFR, MET, MEK, ERK, ALK, RET, KIT, IGFR , TRK and/or FGFR. In some embodiments, the tyrosine kinase inhibitor is an inhibitor of EGFR, VEGF, and/or c-MET. In some embodiments, the tyrosine kinase inhibitor is osimertinib, lenvatinib, axitinib, sunitinib, cabozantinib, XL092, or bevacizumab. In some embodiments, the inhibitor of HIF comprises an inhibitor of HIF-2α. In certain embodiments, the HIF-2α inhibitor is AB521. In some embodiments, the PARP inhibitor is olaparib, rucapanib, or niraparib. In some embodiments, the RAS signaling inhibitor is an inhibitor of KRAS. In some embodiments, immune checkpoint inhibitors inhibit one or more of: PD-1, PD-L1, CTLA-4, LAG-3, TIM-3, and/or TIGIT. In certain embodiments, immune checkpoint inhibitors inhibit one or more of PD-1, PD-L1, or TIGIT. In some embodiments, the immune checkpoint inhibitor includes one or more of the following: cepalizumab, dofenumab, and/or AB308. In some embodiments, agents that target extracellular production of adenosine include one or more of the following: a CD73 inhibitor, a CD39 inhibitor, an _A2AR inhibitor, an _A2BR inhibitor, and/or an _A2AR and inhibitors of _A2BR . In certain embodiments, agents that target extracellular production of adenosine include one or more of: elumelon, quinlistat, and/or AB598. In some embodiments, the chemotherapeutic agent includes one or more of the following: platinum-based, paclitaxel-based, anthracycline-based chemotherapeutic agent, low-dose cytarabine (LDAC), or gemcitabine. In certain embodiments, the chemotherapeutic agent is selected from cisplatin, carboplatin, oxaliplatin, doxorubicin, docetaxel, paclitaxel, nab-paclitaxel, low-dose cytarabine (LDAC ) and gemcitabine. In yet another embodiment, an AXL inhibitor described herein is administered with docetaxel. In yet another embodiment, the AXL inhibitor is administered with a checkpoint inhibitor. In yet another embodiment, the AXL inhibitor is administered in combination with docetaxel and a checkpoint inhibitor, such as cepalizumab.

The selection of additional therapeutic agents may be informed by the current standard of care for the specific cancer and/or the mutation status and/or disease stage of the individual cancer. For example, the National Comprehensive Cancer Network (NCCN) publishes detailed standards of care guidelines. See, for example, NCCN Acute Myeloid Leukemia v1.2022, NCCN Squamous Cell Skin Cancer v.2.2022, NCCN Head and Neck Cancer v.2.2022, NCCN Ovarian/Fallopian Tube/Primary Peritoneal Cancer v.1.2022, NCCN Pancreatic Cancer v. .1.2022, NCCN Bladder Cancer v.1.2022, NCCN Malignant Peritoneal Mesothelioma v.1.2022, NCCN Malignant Pleural Mesothelioma v.1.2022, NCCN Melanoma: Skin v.2.2022, NCCN Melanoma: Uvea v2.2022, NCCN Non-small cell lung cancer v.3.2022, NCCN kidney cancer v.4.2022. pharmaceutical composition

The AXL inhibitors of the present disclosure may be in the form of a composition suitable for administration to an individual. Typically, such compositions are pharmaceutical compositions containing a compound according to the present disclosure or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients. In certain embodiments, an AXL inhibitor can be present in an effective amount. Pharmaceutical compositions can be used in the methods of the present disclosure; thus, for example, pharmaceutical compositions containing compounds according to the present disclosure can be administered to individuals to practice the therapeutic and preventive methods and uses described herein.

In one or more embodiments, the pharmaceutical composition includes an AXL inhibitor according to the present disclosure in an amount between about 10 mg and about 1,000 mg. In one or more embodiments, the pharmaceutical composition includes an AXL inhibitor according to the present disclosure in an amount of between about 10 mg and about 500 mg. In some embodiments, an AXL inhibitor according to the present disclosure is present in an amount between about 10 mg and about 300 mg, such as 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35, mg, 40 mg , 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 190 mg, 195 mg, 200 mg, 205 mg, 210 mg, 215 mg, 220 mg, 225 mg, 230 mg, 235 mg, 240 mg, 245 mg, 250 mg, 255 mg, 260 mg, 265 mg, 270 mg, 275 mg, 280 mg, 285 mg, 290 mg , 295 mg, or 300 mg, 305 mg, 310 mg, 315 mg, 320 mg, 325 mg, 330 mg, 335 mg, 340 mg, 345 mg, 350 mg, 355 mg, 360 mg, 365 mg, 370 mg, 375 mg, 380 mg, 385 mg, 390 mg, 395 mg, 400 mg, 405 mg, 410 mg, 415 mg, 420 mg, 425 mg, 430 mg, 435 mg, 440 mg, 445 mg, 450 mg, 455 mg , 460 mg, 465 mg, 470 mg, 475 mg, 480 mg, 485 mg, 490 mg, 495 mg or 500 mg. In some embodiments, an AXL inhibitor according to the present disclosure is present in an amount of between about 10 mg and about 50 mg. In some embodiments, an AXL inhibitor according to the present disclosure is present in an amount of between about 25 mg and about 75 mg. In some embodiments, AXL inhibitors according to the present disclosure are present in an amount of between about 25 mg and about 50 mg. In some embodiments, AXL inhibitors according to the present disclosure are present in an amount of between about 50 mg and about 100 mg. In some embodiments, AXL inhibitors according to the present disclosure are present in an amount of between about 100 mg and about 200 mg. In some embodiments, AXL inhibitors according to the present disclosure are present in an amount between about 100 mg and about 150 mg. In some embodiments, AXL inhibitors according to the present disclosure are present in an amount between about 150 mg and about 200 mg. In some embodiments, an AXL inhibitor according to the present disclosure is present in an amount of between about 200 mg and about 300 mg. In some embodiments, AXL inhibitors according to the present disclosure are present in an amount of between about 200 mg and about 250 mg. In some embodiments, an AXL inhibitor according to the present disclosure is present in an amount of between about 250 mg and about 300 mg. In some embodiments, an AXL inhibitor according to the present disclosure is present in an amount of between about 300 mg and about 400 mg. In some embodiments, an AXL inhibitor according to the present disclosure is present in an amount of between about 300 mg and about 350 mg. In some embodiments, an AXL inhibitor according to the present disclosure is present in an amount of between about 350 mg and about 400 mg. In some embodiments, an AXL inhibitor according to the present disclosure is present in an amount of between about 400 mg and about 500 mg. In some embodiments, an AXL inhibitor according to the present disclosure is present in an amount of between about 400 mg and about 450 mg. In some embodiments, an AXL inhibitor according to the present disclosure is present in an amount of between about 450 mg and about 500 mg.

Pharmaceutical compositions of the present disclosure may be formulated to be compatible with the intended method or route of administration. Access routes may include those known in the art. Exemplary routes of administration are oral and parenteral. Additionally, pharmaceutical compositions may be used in combination with one or more other therapies described herein to treat or prevent the diseases, conditions, and disorders covered by this disclosure. In one embodiment, one or more other therapeutic agents contemplated by the present disclosure are included in the same pharmaceutical composition comprising an AXL inhibitor according to the present disclosure. In another embodiment, one or more additional therapeutic agents are in a separate composition from the pharmaceutical composition containing an AXL inhibitor according to the present disclosure.

In one aspect, the compounds described herein can be administered orally. Oral administration can be via, for example, capsules or tablets. In preparing pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, tablets or capsules generally include at least one pharmaceutically acceptable excipient. Non-limiting examples of pharmaceutically acceptable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginate, tragacanth, gelatin, silicic acid Calcium, microcrystalline cellulose, polyvinylpyrrolidone, polyethylene glycol, cellulose, sterile water, syrup and methylcellulose. Other pharmaceutically acceptable excipients include lubricants, such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; and preservatives, such as methyl hydroxybenzoate and propyl hydroxybenzoate. ester.

In another aspect, the compounds described herein can be administered parenterally, such as by intravenous injection. Pharmaceutical compositions suitable for parenteral administration may be formulated as injectable solutions or may be reconstituted for injection in an appropriate system such as a physiological solution. Such solutions may include sterile water for injection, saline, buffers, and tonicity excipients in amounts suitable to achieve isotonicity under appropriate physiological conditions.

The pharmaceutical compositions described herein may be stored in one or more suitable sterile containers. In some embodiments, the container is designed to maintain the stability of the pharmaceutical composition over a given period of time. invest

Generally, the disclosed methods comprise administering to an individual in need thereof an effective amount of an AXL inhibitor described herein or a composition thereof. An "effective amount" of an AXL inhibitor with respect to the present disclosure means an amount of compound sufficient to engage the target (by inhibiting or antagonizing the target) at a level indicative of the compound's potency. For AXL, target engagement can be determined by one or more biochemical or cellular assays, yielding an EC50, ED50, EC90, IC50, or similar value that can be used as an assessment of compound potency. Assays to determine target engagement include, but are not limited to, those described in the Examples. An effective amount may be administered as a single amount or as multiple, smaller amounts (eg, as one tablet with an amount of "x", as two tablets each with an amount of "x/2", etc.).

In some embodiments, the disclosed methods comprise administering to an individual in need thereof a therapeutically effective amount of a compound described herein. As used herein, the phrase "therapeutically effective amount" with respect to AXL refers to a dosage regimen (i.e., amounts and intervals) of a compound that provides a specific pharmacological effect for which the compound is administered to an individual in need of such treatment. For prophylactic uses, a therapeutically effective amount is effective to eliminate or reduce the risk, lessen the severity, or delay the onset of the disease, including biochemical, histological and/or behavioral signs or symptoms of the disease. For treatment, a therapeutically effective amount is effective to reduce, ameliorate, or eliminate one or more signs or symptoms associated with the disease, delay the progression of the disease, prolong survival, reduce the dosage of other drugs required to treat the disease, or a combination thereof. For cancer specifically, a therapeutically effective amount may, for example, result in killing of cancer cells, reduction in cancer cell count, reduction in tumor burden, reduction in tumor volume, elimination of tumors or metastases, or reduction in metastatic spread. The therapeutically effective amount may vary based on, for example, one or more of the individual's age and weight, the individual's general health, the stage of the individual's disease, the route of administration, and prior or concomitant treatments.

Administration may include one or more (eg, one, two, or three or more) administration periods.

In certain embodiments, AXL inhibitors contemplated by the present disclosure may range from about 0.01 mg/kg to about 100 mg/kg, or from about 0.1 mg/kg to about 50 mg/kg, or from about 0.1 mg/kg to about 25 mg/kg, or about 0.1 mg/kg to about 15 mg/kg, or about 0.1 mg/kg to about 10 mg/kg, or about 0.1 mg/kg to about 5 mg/kg of an individual's body weight daily, weekly, or every Administer one or more times per month (e.g., oral, parenteral, etc.) to achieve the desired effect. In some embodiments, appropriate body weight-based dosages for compounds contemplated by the present disclosure are used to determine dosages to be administered independent of an individual's weight. In certain embodiments, an AXL inhibitor of the present disclosure is administered (e.g., oral, parenteral, etc.) at a fixed dosage level of about 1 mg to about 1000 mg one or more times daily, weekly, or monthly to Get the desired effect. In some embodiments, an AXL inhibitor according to the present disclosure is administered at a fixed dosage level of between about 10 mg and about 500 mg one or more times per day, per week, or per month to achieve the desired effect. In some embodiments, the AXL inhibitor according to the present disclosure is administered in a dosage of between about 10 mg to about 300 mg, particularly 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35, mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg , 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 105mg, 110mg, 115mg, 120mg, 125mg, 130mg, 135mg, 140mg, 145mg, 150mg, 155mg, 160mg, 165mg, 170mg, 175mg, 180mg, 185mg , 190mg, 195mg, 200mg, 205mg, 210mg, 215mg, 220mg, 225mg, 230mg, 235mg, 240mg, 245mg, 250mg, 255mg, 260mg, 265mg, 270mg, 275mg, 280mg, 285mg, 290mg, 295mg or 300 mg fixed dose level, administered one or more times daily, weekly or monthly to achieve desired results. In some embodiments, an AXL inhibitor according to the present disclosure is administered in an amount between about 10 mg and about 50 mg one or more times per day, per week, or per month to achieve the desired effect. In some embodiments, an AXL inhibitor according to the present disclosure is administered in an amount between about 25 mg and about 75 mg one or more times per day, per week, or per month to achieve the desired effect. In some embodiments, an AXL inhibitor according to the present disclosure is administered in an amount between about 50 mg and about 100 mg one or more times per day, per week, or per month to achieve the desired effect. In some embodiments, an AXL inhibitor according to the present disclosure is administered in an amount between about 100 mg and about 200 mg one or more times per day, per week, or per month to achieve the desired effect. In some embodiments, an AXL inhibitor according to the present disclosure is administered in an amount between about 100 mg and about 150 mg one or more times per day, per week, or per month to achieve the desired effect. In some embodiments, an AXL inhibitor according to the present disclosure is administered in an amount between about 200 mg and about 300 mg one or more times per day, per week, or per month to achieve the desired effect. In some embodiments, an AXL inhibitor according to the present disclosure is administered in an amount between about 250 mg and about 300 mg one or more times per day, per week, or per month to achieve the desired effect.

In some embodiments, AXL inhibitors according to the present disclosure are administered one or more times daily, weekly, or monthly to achieve the desired effect. In some embodiments, the AXL inhibitor is administered once or twice daily. In one embodiment, the AXL inhibitor is administered twice daily. In another embodiment, the AXL inhibitor is administered once daily.

In certain embodiments, the AXL inhibitor is included in a "unit dosage form." The phrase "unit dosage form" means physically discrete units, each unit containing a predetermined amount of an AXL inhibitor sufficient to produce the desired effect, alone or in combination with one or more additional agents. It should be understood that the parameters of the dosage unit form will depend on the specific dosage form and the effect to be achieved. experiment

The following examples are set forth to provide those skilled in the art with a complete disclosure and description of how to make and use the disclosure, and are not intended to limit the scope of what the inventors believe to be their invention. Other compounds within the scope of the present disclosure may be prepared using methods based on those illustrated in these Examples or based on other methods known in the art. Every effort has been made to ensure the accuracy of the figures used (e.g., quantities, temperatures, etc.), but some experimental errors and deviations should be taken into account.

All reactions were performed using a polytetrafluoroethylene-coated magnetic stir bar at the specified temperature and, when specified, under an inert atmosphere. All chemicals were used as received. By TLC (Silicone 60 with fluorescent F254, visualized with short/long wave UV lamp) and/or LCMS (Agilent 1100 or 1200 series LCMS using a binary solvent system [0.1% formic acid in MeCN/0.1% formic acid H ₂ O solution] for UV detection at 254 or 220 nm. The system uses one of the following columns: Agilent Eclipse Plus C18 [3.5 μm, 4.6 mm id × 100 mm], Waters XSelect HSS C18 [3.5 μm, 2.1 mm id × 75 mm]) to monitor the reaction. Flash chromatography was performed on silica using an automated system (CombiFlash RF+ manufactured by Teledyne ISCO) with detection wavelengths of 254 and 280 nm and optionally equipped with an evaporative light scattering detector. Reversed-phase preparative HPLC was performed on an Agilent 1260 or 1290 Infinity Series HPLC. Gradient elution on a Gemini C18 110 Å column (21.2 mm id ×x 250 mm) using a binary solvent system (MeCN/H ₂ O, acid modifier as needed, such as 0.1% TFA or 0.1% formic acid) , dissolve the sample, and perform variable wavelength detection. The final compound obtained via preparative HPLC was concentrated via lyophilization. All reported yields are isolated yields. All compounds characterized were purified to ≥95% purity by H NMR or LCMS (Agilent 1100 or 1200 series LCMS at ²⁵⁴ or 220 nm using a binary solvent system [0.1% formic acid in MeCN/0.1% formic acid H ₂ O solution] for UV detection, the system uses one of the following columns: Agilent Eclipse Plus C18 [3.5 μm, 4.6 mm id × 100 mm], Waters XSelect HSS C18 [3.5 μm, 2.1 mm id × 75 mm ]) determine. ¹ H NMR spectra were recorded on a Varian 400 MHz NMR spectrometer or a Bruker AVANCE NEO 400 MHz NMR. equipped with an Oxford AS400 magnet. Chemical shifts (δ) are reported as parts per million (ppm) relative to residual non-deuterated solvent or tetramethylsilane as an internal reference. The abbreviations s, br s, d, t, q, dd, dt, ddd, dddt and m respectively represent singlet, broad singlet, doublet, triplet, quartet, doublet of doublet, doublet of triplet. , double peaks, double peaks, double peaks and multiple peaks.

Unless otherwise stated, temperatures are in degrees Celsius (°C) and pressures are at or near atmospheric pressure. Use standard abbreviations, including the following: rt or rt = room temperature; min = minutes; h or hr = hours; t = run time; mg = milligram; g = gram; μl or μL = microliter; ml or mL = milliliter; l or L = liter; mM = millimole concentration; M = molar concentration; mol = mole; mmol = millimole; aq. = aqueous; calcd = calculated; sat. = saturated; DCM or CH ₂ Cl ₂ = dichloromethane; DCE = 1,2-dichloroethane; MTBE = methyl tertiary butyl ether; THF = tetrahydrofuran; Et ₂ O = diethyl ether; EtOAc = ethyl acetate; ACN = acetonitrile; AcOH = Acetic acid; TFA = trifluoroacetic acid; NMP = N -methyl-2-pyrrolidinone; DMF = N , N -dimethylformamide; DMSO = dimethylsulfoxide; IPA = isopropyl alcohol; EtOH = ethanol ;MeOH=methanol; m -CPBA=meta-chloroperoxybenzoic acid; _H2 =hydrogen; _N2 =nitrogen; _{NH3 =} ammonia; _Cs2CO3 =cesium carbonate; NaH=sodium hydride; NaBH(OAc) ₃ = sodium triacetyloxyborohydride; NaOH = sodium hydroxide; Na ₂ SO ₄ = sodium sulfate; MgSO ₄ = magnesium sulfate; Na ₂ CO ₃ = sodium carbonate; NaHCO ₃ = sodium bicarbonate; Et ₃ N = triacetate Ethylamine; MeMgBr=methylmagnesium bromide; LDA=lithium diisopropylamide; DIPEA= N,N -diisopropylethylamine; DMEDA= N , N -dimethylethane-1,2- Diamine; SEMCl=2-(trimethylsilyl)ethoxymethyl chloride; HATU= N -[(dimethylamino)-1 H -1,2,3-triazolo-[ 4,5- b ]pyridin-1-ylmethylene]- N -methylcarboxylammonium hexafluorophosphate N -oxide; EDC=1-ethyl-3-(3-dimethylaminopropyl) Carbodiimide; HOBt = hydroxybenzotriazole; NBS = N -bromosuccinimide; KOAc = potassium acetate; K ₃ PO ₄ = potassium phosphate; K ₂ CO ₃ = potassium carbonate; TFA = trifluoroacetic acid; MeI=methane iodide; PdCl ₂ (dppf) or (dppf) PdCl ₂ =[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride; XPhos Pd G3=(2- Dicyclohexylphosphine-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]methanesulfonate Palladium( _II ) acid _; ) dipalladium (0); Pd(PPh ₃ ) ₄ = tetrakis (triphenylphosphine) palladium (0); B ₂ pin ₂ = bis (pinacol) diboron; MHz = megahertz; Hz = Hertz; ppm = parts per million; ESI-MS = electrospray ionization mass spectrometry; NMR = nuclear magnetic resonance. Examples Example 1 : 6-[( 7S )-2-{3-[4-(3- methylpyridin -2- yl ) phenyl ] -1H - pyrrolo [2,3- b ] pyridine -5 -yl } -6,7,8,9 - tetrahydro - 5H - benzo [7] annen -7- yl ]-3- oxa -6- azabicyclo [3.1.1] heptane

Step a : To a mixture of 3-oxa-6-aza-bicyclo[3.1.1]heptane 4-toluenesulfonic acid (5.00 g, 18.4 mmol) in CH ₂ Cl ₂ (92 mL) at room temperature 2-Bromo-5,6,8,9-tetrahydro-benzocyclohepten-7-one (4.63 g, 19.4 mmol) was added, followed by NaBH(OAc) ₃ (4.69 g, 22.1 mmol). The reaction mixture was then stirred at room temperature for 4 hours. Additional NaBH(OAc) ₃ (4.69 g each) was added at t = 4 hours and t = 8 hours. After the last addition, the reaction mixture was stirred for a further 4 hours at room temperature. The reaction mixture was diluted with _{CH2Cl2 (} 250 mL), water (250 mL) and 2 M NaOH _(aq) (100 mL, or until pH > 12) and stirred. The organic phase was washed with 4:1:1 water:brine:2 M NaOH _(aq) (300 mL), dried _{over Na2SO4} , and concentrated. The crude material was purified by silica gel chromatography (Hexane: (EtOAc + 1% Et ₃ N) 0 to 100% gradient) to afford the racemic product as a white solid (5.13 g, 86%). Resolution of external elimination using chiral HPLC (Daicel CHIRALPAK IA; MeOH/DEA 100/0.1 v/v; 1.0 mL/min; UV 230 nm; 5.3 min (desired isomer), 7.0 min (other isomers)) Swirl the mixture.

Step b : To a mixture of 2-bromo-3-methylpyridine (2.0 g, 12 mmol), (4-chlorophenyl)boronic acid (1.82 g, 11.6 mmol) and Na ₂ CO ₃ (2.46 g, 23.2 mmol) Add dioxane (64 mL) and water (14 mL). The suspension was degassed with nitrogen for 10 min and _PdCl2 (dppf) (425 mg, 0.581 mmol) was added. The reaction mixture was stirred at 95 °C for 16 h, cooled, diluted with EtOAc (15 mL), dried over MgSO, filtered through _celite , and concentrated. The crude material was purified by silica gel chromatography (Hexane:EtOAc 0 to 100% gradient) to afford the desired product as an off-white solid (2.0 g, 86%).

Step c : To the mixture _of product from step _b (2.0 g, 9.8 mmol), _B2pin2 (5 g, 20 mmol) and _K3PO4 (5.22 g, 24.6 mmol) was added dioxane (100 mL ). The suspension was degassed with nitrogen for 10 minutes and XPhos Pd G3 (834 mg, 0.985 mmol) was added. The reaction mixture was stirred at 95°C for 16 h, cooled, diluted with EtOAc (15 mL), filtered through celite, and concentrated to give the desired product, which was used as crude in step d.

Step d : Add the product of step c (4.9 mmol), 1-(benzenesulfonyl)-5-bromo-3-iodopyrrolo[2,3- b ]pyridine (2.26 g, 4.88 mmol) and K ₂ CO To the mixture of ₃ (1.35 g, 9.77 mmol), dioxane (30 mL) and water (5 mL) were added. The suspension was degassed with nitrogen for 10 minutes and _PdCl2 (dppf) (180 mg, 0.245 mmol) was added. The reaction mixture was stirred at 80°C for 4 hours, cooled, diluted with _CH2Cl2 (15 mL), dried over _MgSO4 , filtered through _celite , and concentrated. The crude material was purified by silica gel chromatography (Hexane:EtOAc 0 to 100% gradient) to afford the desired product as an off-white solid (1.8 g, 73%, two steps).

Step e : To a mixture of product from step d (350 mg, 0.694 mmol), _B2pin2 (353 mg, 1.39 mmol) and KOAc (136 mg _, 1.39 mmol) was added dioxane (7 mL). The suspension was degassed with nitrogen for 10 minutes and _PdCl2 (dppf) (26 mg, 0.035 mmol) was added. The reaction mixture was stirred at 95°C for 16 hours, cooled, diluted with EtOAc, filtered through celite, and concentrated to give the desired product, which was used as crude in step f.

Step f : To the product of step e (0.694 mmol), 6-[(7 S )-3-bromo-6,7,8,9-tetrahydro- 5H -benzo[7]annen-7-yl Dioxane (5.8 mL) was added to a mixture of ]-3-oxa-6-azabicyclo[3.1.1]heptane (222 mg, 0.689 mmol) and K ₂ CO ₃ (192 mg, 1.39 mmol) and water (1.2 mL). The suspension was degassed with nitrogen for 10 minutes and _PdCl2 (dppf) (26 mg, 0.035 mmol) was added. The reaction mixture was stirred at 95°C for ₃ hours, cooled, diluted with _CH2Cl2 (15 mL), dried over _MgSO4 , filtered through celite, and concentrated. The crude material was purified by silica gel chromatography ((CH ₂ Cl ₂ :MeOH) + 1% NH _{3 (aq , 28 wt%)} 0 to 10% gradient) to afford the desired product as a white solid (302 mg, 65% , two steps).

Step g : To a solution of the product from step f (280 mg, 0.420 mmol) in dioxane (4 mL) was added 6 M NaOH _(aq) (84 mg, 2.1 mmol). The reaction mixture was stirred at 90°C for 2 hours, cooled, diluted with water, and extracted with _CH2Cl2 (3 _x 50 mL). The combined organic phases were dried over _MgSO4 and concentrated. The crude material was purified by C18 reverse phase chromatography ((water:ACN) + 1% TFA 0 to 70% gradient) before partial concentration and addition of _{K2CO3 .} The mixture was extracted with _CH2Cl2 (3 _x 50 mL). The combined organic phases were dried over _MgSO4 and concentrated to give the desired product as a white solid (199 mg, 90%). ¹ H NMR (400 MHz, chloroform- d ) δ 10.78 (s, 1H), 8.61 (d, J = 2.0 Hz, 1H), 8.55 (ddd, J = 4.7, 1.7, 0.7 Hz, 1H), 8.43 (d , J = 2.0 Hz, 1H), 7.79 – 7.71 (m, 2H), 7.67 – 7.55 (m, 4H), 7.39 (d, J = 6.5 Hz, 2H), 7.22 – 7.15 (m, 2H), 4.30 ( d, J = 10.8 Hz, 2H), 3.74 (d, J = 10.8 Hz, 2H), 3.70 (d, J = 6.0 Hz, 2H), 3.27 (dd, J = 11.1, 7.8 Hz, 1H), 2.97 ( m, 2H), 2.83 (q, J = 12.9 Hz, 2H), 2.65 – 2.56 (m, 1H), 2.43 (s, 3H), 1.93 (d, J = 8.1 Hz, 2H), 1.85 (d, J = 8.4 Hz, 1H), 1.37 (m, 2H). ESI MS [M+H] ⁺ for C ₃₅ H ₃₅ N ₄ O, calculated 527.3, found 527.3. Example 2 : 6-[( 7S )-2-{3-[4-(3- methylpyridin -2- yl ) phenyl ] -2H - pyrazolo [3,4- b ] pyridine -5 -yl } -6,7,8,9 - tetrahydro - 5H - benzo [7] annen -7- yl ]-3- oxa -6- azabicyclo [3.1.1] heptane

Steps a and b : The compound formed in step b is prepared in a manner similar to that described in Example 1, steps b and c.

Step c : To the product from step b (4.9 mmol), 5-bromo-3-iodo-1-(oxan-2-yl)pyrazolo[3,4- b ]pyridine (2.0 g, Dioxane (30 mL) and water (5 mL) were added to a mixture of 4.9 mmol) and K ₂ CO ₃ (1.35 g, 9.8 mmol). The suspension was degassed with nitrogen for 10 minutes and _PdCl2 (dppf) (180 mg, 0.245 mmol) was added. The reaction mixture was stirred at 80°C for 4 hours, cooled, diluted with _CH2Cl2 (15 mL), dried over _MgSO4 , filtered through _celite , and concentrated. The crude material was purified by silica gel chromatography (Hexane:EtOAc 0 to 100% gradient) to afford the desired product as an off-white solid (1.5 g, 68%, two steps).

Step d : To the mixture of product from step c (250 mg, 0.556 mmol), _B2pin2 (283 mg, 1.11 mmol) and _KOAc (110 mg, 1.11 mmol) was added dioxane (6 mL). The suspension was degassed with nitrogen for 10 minutes and _PdCl2 (dppf) (20 mg, 0.027 mmol) was added. The reaction mixture was stirred at 95°C for 16 h, cooled, diluted with EtOAc (10 mL), filtered through celite, and concentrated to give the desired product, which was used as crude in step c.

Step e : To the product from step d (0.556 mmol), 6-[( 7S )-3-bromo-6,7,8,9-tetrahydro- 5H -benzo[7]annene-7- Dioxane (5 mL) was added to a mixture of [3-oxa-6-azabicyclo[3.1.1]heptane (177 mg, 0.549 mmol) and K ₂ CO ₃ (153 mg, 1.11 mmol). and water (1 mL). The suspension was degassed with nitrogen for 10 minutes and _PdCl2 (dppf) (20 mg, 0.027 mmol) was added. The reaction mixture was stirred at 95°C for ₃ hours, cooled, diluted with _CH2Cl2 (15 mL), dried over _MgSO4 , filtered through celite, and concentrated. The crude material was purified by silica gel chromatography ((CH ₂ Cl ₂ :MeOH) + 1% NH _{3 (aq , 28 wt%)} 0 to 10% gradient) to afford the desired product as a white solid (218 mg, 65% , two steps).

Step f : To a solution of _the product from step e (200 mg, 0.327 mmol) in _CH2Cl2 (4 mL) was added TFA (2 mL). The reaction mixture was stirred at room temperature for 16 hours and concentrated. The crude material was purified by C18 reverse phase chromatography ((water:ACN) + 1% TFA 0 to 70% gradient) before partial concentration and addition _{of K2CO3} . The mixture was extracted with _CH2Cl2 (3 _x 50 mL). The combined organic phases were dried over _MgSO4 and concentrated to give the desired product as a white solid (152 mg, 88%). ¹ H NMR (400 MHz, chloroform- d ) δ 12.87 (s, 1H), 8.85 (d, J = 2.1 Hz, 1H), 8.55 (ddd, J = 4.8, 1.7, 0.7 Hz, 1H), 8.51 (d , J = 2.1 Hz, 1H), 8.12 – 8.04 (m, 2H), 7.74 – 7.66 (m, 2H), 7.60 (ddt, J = 7.7, 1.8, 0.8 Hz, 1H), 7.38 (d, J = 6.3 Hz, 2H), 7.24 – 7.17 (m, 2H), 4.31 (d, J = 10.7 Hz, 2H), 3.73 (d, J = 10.7 Hz, 2H), 3.67 (d, J = 6.1 Hz, 2H), 3.31 – 3.21 (m, 1H), 3.04 – 2.91 (m, 2H), 2.85 (q, J = 12.2 Hz, 2H), 2.56 (q, J = 6.7 Hz, 1H), 2.42 (s, 3H), 1.96 (d, J = 12.2 Hz, 2H), 1.84 (d, J = 8.3 Hz, 1H), 1.37 (q, J = 11.3 Hz, 2H). ESI MS [M+H] ⁺ for C ₃₄ H ₃₄ N ₅ O, calculated 528.3, found 528.2. Example 3 : 6-[(7 S )-2-(3-{4-[3-(2- methoxyethoxy ) pyridin -2- yl ] phenyl }-1 H -pyrrolo [2, 3- b ] Pyridin -5- yl )-6,7,8,9- tetrahydro - 5H - benzo [7] annen -7- yl ]-3- oxa -6- azabicyclo [3.1 .1] heptane

Step a : To a solution of 2-bromopyridin-3-ol (2.0 g, 11 mmol) in DMF (25 mL) at room temperature was added K ₂ CO ₃ (3.17 g, 22.9 mmol) and 1-bromo- 2-Methoxyethane (2.4 g, 17 mmol). The reaction mixture was stirred at 80 °C for 16 h, cooled, diluted with MTBE, filtered through celite, washed _twice with water, dried over MgSO, and concentrated to give the desired product (assumed 11 mmol) without any further Purification is used in the next step.

Step bg : The title compound was prepared using step bg in a similar manner to Example 1. ¹ H NMR (400 MHz, chloroform- d ) δ 10.55 (d, J = 2.4 Hz, 1H), 8.61 (d, J = 2.0 Hz, 1H), 8.44 (d, J = 2.0 Hz, 1H), 8.34 ( dd, J = 4.6, 1.4 Hz, 1H), 8.15 – 8.07 (m, 2H), 7.79 – 7.70 (m, 2H), 7.61 (d, J = 2.4 Hz, 1H), 7.39 (dq, J = 3.4, 2.0 Hz, 2H), 7.32 (dd, J = 8.3, 1.4 Hz, 1H), 7.23 – 7.18 (m, 2H), 4.30 (d, J = 10.7 Hz, 2H), 4.22 – 4.15 (m, 2H), 3.81 – 3.68 (m, 4H), 3.65 (d, J = 6.1 Hz, 2H), 3.43 (s, 3H), 3.24 (d, J = 9.8 Hz, 1H), 2.98 (m, 2H), 2.84 (q , J = 13.1 Hz, 2H), 2.56 (q, J = 6.8 Hz, 1H), 1.98 (d, J = 5.0 Hz, 2H), 1.83 (d, J = 8.3 Hz, 1H), 1.34 (p, J = 10.0 Hz, 2H). ESI MS [M+H] ⁺ for C ₃₇ H ₃₉ N ₄ O ₃ , calculated 587.3, found 587.3. Example 4 : 6-[(7 S )-2-(3-{4-[3-( pyrrolidin -1- carbonyl ) pyridin -2- yl ] phenyl }-1 H -pyrazolo [3,4 - b ] pyridin -5- yl )-6,7,8,9- tetrahydro -5 H -benzo [7] annen -7- yl ]-3- oxa -6- azabicyclo [3.1. 1] Heptane

Step a : To a stirred solution of 2-bromopyridine-3-carboxylic acid (1.0 g, 5.0 mmol) in DMF (10 mL) was added HATU (2.48 g, 6.52 mmol), diisopropyl ethylamine (1.3 mL, 7.5 mmol) and pyrrolidine (0.45 mL, 5.5 mmol). The reaction mixture was stirred at room temperature for 16 hours, diluted with water (50 mL), and extracted with EtOAc (3 x 50 mL). The combined organic phases were dried over _MgSO4 and concentrated. The crude material was purified by silica gel chromatography (Hexane:EtOAc 0 to 100% gradient) to afford the desired product as a white solid (755 mg, 60%).

Step bg : Prepare the title compound in a similar manner to Example 2. ¹ H NMR (400 MHz, chloroform- d ) δ 12.15 (s, 1H), 8.85 (d, J = 2.0 Hz, 1H), 8.76 (dd, J = 4.8, 1.7 Hz, 1H), 8.51 (d, J = 2.0 Hz, 1H), 8.15 – 8.07 (m, 2H), 8.01 – 7.93 (m, 2H), 7.80 (dd, J = 7.7, 1.7 Hz, 1H), 7.43 – 7.30 (m, 3H), 7.24 ( m, 1H), 4.34 – 4.26 (m, 2H), 3.73 (d, J = 10.7 Hz, 2H), 3.65 (d, J = 6.1 Hz, 2H), 3.51 (bs, 1H), 3.31 – 3.22 (m , 1H), 3.07 – 2.73 (m, 5H), 2.57 (q, J = 6.7 Hz, 1H), 1.96 (d, J = 11.6 Hz, 2H), 1.84 (d, J = 8.3 Hz, 1H), 1.79 – 1.63 (m, 5H), 1.54 (bs, 1H), 1.36 (d, J = 12.3 Hz, 2H). ESI MS [M+H] ⁺ for C ₃₈ H ₃₉ N ₆ O ₂ , calculated 611.3, found 611.3. Example 5 : 6-[(7 S )-2-(3-{4-[3-( morpholin -4- yl ) pyridin -2- yl ] phenyl }-1 H -pyrrolo [2,3- b ] Pyridin -5- yl )-6,7,8,9- tetrahydro - 5H - benzo [7] annen -7- yl ]-3- oxa -6- azabicyclo [3.1.1 ] Heptane

Step a : To a mixture of 2-bromo-3-iodopyridine (2.0 g, 7.0 mmol), morpholine (668 µL, 7.75 mmol) and Cs ₂ CO ₃ (2.52 g, 7.75 mmol), add toluene (20 mL) . The suspension was degassed with nitrogen for 10 minutes and Xantphos (611 mg, 1.06 mmol) and _Pd2dba3 ( ₃₂₂ mg, 0.352 mmol) were added. The reaction mixture was stirred at 90°C for 16 hours, cooled, diluted with EtOAc (10 mL), filtered through celite, and concentrated. The crude material was purified by silica gel chromatography (Hexane:EtOAc 0 to 100% gradient) to afford the desired product (342 mg, 20%).

Step bg : The title compound was prepared using step bg in a similar manner to Example 1. ¹ H NMR (400 MHz, chloroform- d ) δ 11.37 (d, J = 2.4 Hz, 1H), 8.65 – 8.60 (m, 1H), 8.44 (d, J = 2.0 Hz, 1H), 8.38 (dd, J = 4.6, 1.4 Hz, 1H), 8.14 – 8.06 (m, 2H), 7.79 – 7.71 (m, 2H), 7.64 (d, J = 2.3 Hz, 1H), 7.39 (dq, J = 3.9, 2.0 Hz, 2H), 7.33 (dd, J = 8.2, 1.5 Hz, 1H), 7.27 – 7.14 (m, 2H), 4.30 (d, J = 10.7 Hz, 2H), 3.76 – 3.67 (m, 6H), 3.67 – 3.61 (m, 2H), 3.29 – 3.19 (m, 1H), 3.05 – 2.78 (m, 8H), 2.54 (q, J = 6.7 Hz, 1H), 1.93 (bs, 2H), 1.83 (d, J = 8.2 Hz, 1H), 1.33 (p, J = 10.0 Hz, 2H). ESI MS [M+H] ⁺ for C ₃₈ H ₄₀ N ₅ O ₂ , calculated 598.3, found 598.3. Example 6 : N,N - dimethyl -2-(4-{5-[(7 S )-7-{3- oxa -6- azabicyclo [3.1.1] hept -6- yl }- 6,7,8,9- tetrahydro -5 H -benzo [7] annen - 2- yl ]-1 H -pyrrolo [2,3- b ] pyridin -3- yl } phenyl ) pyridine- 3- Sulfonamide

Step a : To a stirred solution of 2-bromopyridine-3-sulfonyl chloride (2.5 g, 9.7 mmol) in THF (50 mL) at 0°C was added N , N -dimethylamine (5.89 mL , 11.8 mmol, 2 M in THF). The reaction mixture was stirred at room temperature for 16 hours and concentrated. The crude material was purified by silica gel chromatography (Hexane:EtOAc 0 to 70% gradient) to afford the desired product as an off-white solid (1.1 g, 35%).

Step bg : The title compound was prepared using step bg in a similar manner to Example 1. ¹ H NMR (400 MHz, chloroform- d ) δ 11.52 (s, 1H), 8.82 (dd, J = 4.8, 1.7 Hz, 1H), 8.61 (d, J = 2.1 Hz, 1H), 8.47 – 8.39 (m , 2H), 7.81 – 7.73 (m, 2H), 7.73 – 7.65 (m, 2H), 7.62 (d, J = 1.3 Hz, 1H), 7.48 – 7.35 (m, 3H), 7.24 – 7.17 (m, 1H ), 4.30 (d, J = 10.7 Hz, 2H), 3.78 – 3.65 (m, 4H), 3.31 – 3.21 (m, 1H), 3.05 – 2.76 (m, 4H), 2.60 (dd, J = 9.4, 4.8 Hz, 1H), 2.39 (s, 6H), 1.99 – 1.91 (m, 2H), 1.84 (d, J = 8.4 Hz, 1H), 1.36 (p, J = 10.6 Hz, 2H). ESI MS [M+H] ⁺ for C ₃₆ H ₃₈ N ₅ O ₃ S, calculated 620.3, found 620.3. Example 7 : 1-[2-(4-{5-[(7 S )-7-{3- oxa -6- azabicyclo [3.1.1] hept -6- yl }-6,7,8 ,9- tetrahydro -5 H -benzo [7] annen -2- yl ]-1 H -pyrrolo [2,3- b ] pyridin -3- yl } phenyl ) pyridin -3- yl ] pyrrole din -2- one

Step a : To a stirred solution of 2-bromo-3-fluoropyridine (5.0 g, 28 mmol) in DMF (60 mL) at 0°C was added 2-pyrrolidone (3.62 g, 42.5 mmol) and NaH (1.5 g, 38 mmol, 60 wt% in oil). The reaction mixture was stirred at 0°C for 15 min and at 85°C for 16 h, cooled, diluted carefully with water (50 mL), and extracted with EtOAc (3 x 50 mL). The combined organic phases were dried over _MgSO4 and concentrated. The crude material was purified by silica gel chromatography (Hexane:EtOAc 0 to 100% gradient) to give the desired product (3.8 g, 55%).

Step bg : The title compound was prepared using step bg in a similar manner to Example 1. ¹ H NMR (400 MHz, chloroform- d ) δ 11.17 (s, 1H), 8.64 (dd, J = 4.7, 1.6 Hz, 1H), 8.56 (d, J = 2.0 Hz, 1H), 8.38 (d, J = 2.0 Hz, 1H), 7.77-7.66 (m, 5H), 7.62 (s, 1H), 7.39-7.30 (m, 2H), 7.22-7.13 (m, 2H), 4.34 (d, J = 11.8 Hz, 2H), 4.12 (s, 2H), 3.90 (d, J = 11.7 Hz, 2H), 3.35 (t, J = 7.0 Hz, 3H), 3.01 – 2.70 (m, 5H), 2.50 (t, J = 8.1 Hz, 2H), 1.97 (m, 5H), 1.52 (s, 2H). ESI MS [M+H] ⁺ for C ₃₈ H ₃₈ N ₅ O ₂ , calculated 596.3, found 596.3. Example 8 : 2-[5- methyl -6-(4-{5-[(7 S )-7-{3- oxa- 6- azabicyclo [3.1.1] hept -6- yl }- 6,7,8,9- tetrahydro -5 H -benzo [7] annen - 2- yl ]-1 H -pyrrolo [2,3- b ] pyridin -3- yl } phenyl ) pyridine- 2- yl ] propan -2- ol

Step a : To a stirred solution of 6-chloro-5-methylpyridine-2-carboxylic acid methyl ester (1.0 g, 5.4 mmol) in THF (20 mL) at -15 °C was added methyl bromide Magnesium (8.9 mL, 27 mmol, 3 M in ether). The reaction mixture was stirred at -15°C for 15 min and at room temperature for 16 h, quenched with saturated NH ₄ Cl _(aq) (50 mL), and extracted with EtOAc (3 x 50 mL). The combined organic phases were dried over _MgSO4 and concentrated to give the desired product (assumed 5.4 mmol), which was used in the next step without any further purification.

Step bg : The title compound was prepared using step bg in a similar manner to Example 1. ¹ H NMR (400 MHz, chloroform- d ) δ 10.88 (s, 1H), 8.58 – 8.53 (m, 1H), 8.46 – 8.40 (m, 1H), 7.79 – 7.63 (m, 4H), 7.63 – 7.54 ( m, 2H), 7.42 – 7.32 (m, 2H), 7.27 – 7.14 (m, 2H), 5.66 (s, 1H), 4.33 (d, J = 11.3 Hz, 2H), 3.93 (d, J = 5.7 Hz , 2H), 3.84 (d, J = 11.4 Hz, 2H), 3.37 – 3.27 (m, 1H), 2.99 – 2.75 (m, 5H), 2.43 (s, 3H), 2.02 – 1.88 (m, 3H), 1.56 (s, 6H), 1.46 (bs, 2H). ESI MS [M+H] ⁺ for C ₃₈ H ₄₁ N ₄ O ₂ , calculated 585.3, found 585.3. Example 9 : 3,6- dimethyl -6'-{5-[(7 S )-7-[(1 R )-3- oxa -6- azabicyclo [3.1.1] hept -6- base ]-6,7,8,9- tetrahydro - 5H - benzo [7] annen -2- yl ] -1H - pyrazolo [3,4- b ] pyridin -3- yl }- 2,3'- bipyridine

Step a : To a solution of 3-bromo-5-chloro-1 H -pyrazolo[3,4- b ]pyridine (10 g, 43 mmol) in DMF (150 mL) at 0 °C was added K ₂ CO ₃ (17.88 g, 129.6 mmol). The mixture was stirred at 0°C for 30 minutes. Triphenylmethane chloride (14.45 g, 51.84 mmol) was added to the above reaction mixture at 0°C. The mixture was stirred at rt for 16 hours and water (100 mL) was added. The aqueous phase was extracted with EtOAc (3 x 60 mL). The combined organic phases were washed with brine (50 mL), dried over MgSO ₄ , concentrated, and purified by silica gel chromatography (Hexane:EtOAc 0 to 20% gradient) to afford the desired product as a white solid (15.98 g, 78%).

Step b : Combine the product from step a (269 mg, 0.566 mmol), _B2pin2 (144 mg, 0.566 mmol), _{PdCl2 (} dppf) (20.7 mg, 0.0283 mmol) and KOAc (111 mg, 1.13 mmol) The mixture was placed under nitrogen. Degassed dioxane (20 mL) was added and the reaction mixture was stirred at 100°C for 4 hours. The mixture was cooled to rt, concentrated, diluted with _CH2Cl2 (50 mL), filtered through celite to remove solids, and concentrated again to give the desired product, which was used as crude in _step d.

Step c : 2-Chloro-5-pyridineboronic acid (789 mg, 5.01 mmol), 2-chloro-3,6-dimethylpyridine (708 mg, 5.00 mmol), PdCl ₂ (dppf) (183 mg, 0.250 mmol) and K ₂ CO ₃ (1.38 g, 10.0 mmol) were added with degassed dioxane (20 mL) and degassed water (5 mL). The reaction mixture was stirred at 95°C for 16 hours, cooled, _concentrated , diluted with _CH2Cl2 (25 mL), dried over _MgSO4 , and concentrated. The crude material was purified by silica gel chromatography (Hexane:EtOAc 0 to 20% gradient) to afford the desired product as a white solid (547 mg, 50%).

Step d : To the product from step b (assumed 0.566 mmol), the product from step c (103 mg, 0.471 mmol), PdCl ₂ (dppf) (17.2 mg, 0.0236 mmol) and K ₂ CO ₃ (130 mg, 0.942 mmol), degassed dioxane (2.4 mL) and degassed water (0.48 mL) were added. The reaction mixture was stirred at 100°C for 16 hours, cooled, _concentrated , diluted with _CH2Cl2 (25 mL), dried over _MgSO4 , and concentrated. The crude material was purified by silica gel chromatography (Hexane:EtOAc 0 to 20% gradient) to afford the desired product as a white solid (81.2 mg, 30%).

Step e : Combine the product from step d (81.2 mg, 0.140 mmol), B _2p in ₂ (42.7 mg, 0.168 mmol), K ₃ PO ₄ (59.4 mg, 0.280 mmol) and XPhos Pd G3 (5.9 mg, 0.0070 mmol). ) mixture was placed under nitrogen. Degassed dioxane (0.7 mL) was added and the mixture was purged with nitrogen for 10 minutes. The reaction mixture was stirred at 100°C for 2 hours, cooled, concentrated, diluted with _CH2Cl2 (10 mL), filtered through celite to remove solids, and concentrated again to give the desired product, which was used in _step f Crude products.

Step f : To the product from step e (assumed 0.140 mmol), 6-[( 7S )-3-bromo-6,7,8,9-tetrahydro- 5H -benzo[7]wheel En-7-yl]-3-oxa-6-azabicyclo[3.1.1]heptane (45.1 mg, 0.140 mmol), PdCl ₂ (dppf) (5.1 mg, 0.0070 mmol) and K ₂ CO ₃ ( To the mixture of 38.7 mg, 0.280 mmol), degassed dioxane (0.7 mL) and degassed water (0.14 mL) were added. The reaction mixture was stirred at 95° _C for 16 hours, cooled, concentrated, diluted with _CH2Cl2 (10 mL), dried over _MgSO4 , and concentrated. The crude material was purified by silica gel chromatography ( _CH2Cl2 : _MeOH 0 to 15% gradient) to afford the desired product as a gray solid (89 mg, 81%).

Step g : To a mixture of the product from step f (89 mg, 0.11 mmol) and CH ₂ Cl ₂ (10 mL) was added triethylsilane (66.3 mg, 0.570 mmol) at 0 °C, followed by slow addition dropwise TFA (65.0 mg, 0.570 mmol). The reaction mixture was stirred at room temperature for 1 hour and concentrated. The crude material was purified by silica gel chromatography (CH ₂ Cl ₂ :MeOH 0 to 15% gradient) to afford the desired product as a white solid (42.3 mg, 69% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.03 (d, J = 2.2 Hz, 1H), 8.92 (dd, J = 2.3, 0.9 Hz, 1H), 8.85 (d, J = 2.2 Hz, 1H) , 8.26 (dd, J = 8.3, 0.9 Hz, 1H), 8.09 (dd, J = 8.2, 2.3 Hz, 1H), 7.64 (d, J = 7.8 Hz, 1H), 7.51 (s, 1H), 7.48 – 7.43 (m, 1H), 7.24 (d, J = 7.8 Hz, 1H), 7.20 (d, J = 7.8 Hz, 1H), 4.13 (d, J = 10.7 Hz, 2H), 3.53 (dd, J = 18.8 , 8.3 Hz, 4H), 3.21 – 3.10 (m, 1H), 3.04 – 2.85 (m, 2H), 2.77 (q, J = 14.4 Hz, 2H), 2.48 – 2.45 (m, 3H), 2.40 – 2.26 ( m, 4H), 1.91 – 1.75 (m, 2H), 1.65 (d, J = 8.0 Hz, 1H), 1.26 – 1.08 (m, 2H). ESI MS [M+H] ⁺ for C ₃₄ H ₃₅ N ₆ O, calculated 543.3, found 543.3. Example 10 : 2-[2-(4-{5-[(7 S )-7-{3- oxa -6- azabicyclo [3.1.1] hept -6- yl }-6,7,8 ,9- tetrahydro -5 H -benzo [7] annen -2- yl ]-1 H -pyrazolo [3,4- b ] pyridin -3- yl } phenyl ) pyridin -3- yl ] Propan -2- ol

Step a : Combine 2-bromonicotinic acid methyl ester (1.71 g, 10.0 mmol), 4-chlorophenylboronic acid (1.56 g, 10.0 mmol), K ₂ CO ₃ (2.76 g, 20.0 mmol) and PdCl ₂ (dppf ) (365 mg, 0.500 mmol) was placed under nitrogen. Degassed dioxane (25 mL) and degassed water (25 mL) were added and the reaction mixture was stirred at 95°C for 4 hours. The mixture was cooled to rt, _concentrated , diluted with _CH2Cl2 (25 mL), dried over _MgSO4 , and concentrated. The crude material was purified by silica gel chromatography (Hexane:EtOAc 0 to 20% gradient) to afford the desired product (2 g, 80%) as a colorless liquid.

Step b : To a solution of the product from step a (2 g, 8 mmol) in THF (20 mL) was added methylmagnesium bromide (8.0 mL, 24 mmol, 3 M in diethyl ether) dropwise at 0 °C. ). The mixture was stirred at rt for 16 hours. Saturated NHCl _(aq) (20 mL) was added and the mixture was extracted with EtOAc (2 x 20 mL). The combined organic phases were washed with brine (20 mL), dried over _Na2SO4 , _filtered , and concentrated to give the desired product (1.6 g, 65%).

Step c : Combine product from step b (1.3 g, 5.2 mmol), B ₂ pin ₂ (2.66 g, 10.4 mmol), K ₃ PO ₄ (2.77 g, 13.1 mmol), XPhos Pd G3 (221 mg, 0.260 mmol) ) and dioxane (50 mL) was purged with nitrogen for 10 minutes. The reaction mixture was stirred at 100 °C for 16 h, cooled to rt, concentrated, diluted with CH ₂ Cl ₂ (50 mL), filtered through celite to remove solids, and concentrated again to give the desired product, which was used in the next step Make crude products.

Step dg : Prepare the title compound in a similar manner to Example 2. ¹ H NMR (400 MHz, chloroform- d ) δ 11.53 (s, 1H), 8.83 (d, J = 2.0 Hz, 1H), 8.55 (dd, J = 4.7, 1.6 Hz, 1H), 8.48 (d, J = 2.0 Hz, 1H), 8.09 – 8.02 (m, 2H), 7.59 – 7.52 (m, 2H), 7.40 – 7.35 (m, 2H), 7.32 (dd, J = 8.1, 4.7 Hz, 1H), 7.22 ( s, 1H), 4.30 (d, J = 10.7 Hz, 2H), 3.72 (d, J = 10.7 Hz, 2H), 3.64 (d, J = 6.1 Hz, 2H), 3.25 (t, J = 9.6 Hz, 1H), 3.03-2.94 (m, 2H), 2.85 (q, J = 13.1 Hz, 2H), 2.56 (q, J = 6.8 Hz, 1H), 1.94 (brs, 2H), 1.85-1.83 (m, 2H ), 1.52 (s, 6H), 1.41 – 1.23 (m, 2H), 0.91 – 0.82 (m, 1H). ESI MS [M+H] ⁺ for C ₃₆ H ₃₈ N ₅ O ₂ , calculated 572.3, found 572.3. Example 11 : 6-[( 7S )-2-{3-[4-(3- methyl - 4H -1,2,4- triazol -4- yl ) phenyl ] -1H - pyrazole And [3,4- b ] pyridin -5- yl }-6,7,8,9 - tetrahydro -5 H -benzo [7] annen -7- yl ]-3- oxa -6- nitrogen Heterobicyclo [3.1.1] heptane

Step a : To a solution of hydrazine acetate (740 mg, 10.0 mmol) and ACN (4 mL) was added dimethylacetamide dimethyl acetal (1.2 g, 10 mmol) at rt. The reaction mixture was stirred at 50°C for 30 minutes. A solution of 4-bromoaniline (1.72 mg, 10.0 mmol) in ACN (4 mL) was added, followed by acetic acid (3 mL). The reaction mixture was then stirred at 120°C for 3 hours, cooled, concentrated, and purified by silica gel chromatography (100% EtOAc, then 95% EtOAc/5% 0.7 M ammonia in methanol) to give the desired product (832 mg , 35%).

Step bf : Prepare the title compound in a manner similar to Example 2, Step bf. ¹ H NMR (400 MHz, chloroform- d ) δ 12.17 (s, 1H), 8.84 (d, J = 2.0 Hz, 1H), 8.46 (d, J = 2.0 Hz, 1H), 8.28 (s, 1H), 8.24 – 8.12 (m, 2H), 7.52 – 7.40 (m, 2H), 7.37 (d, J = 7.2 Hz, 2H), 7.24 (s, 1H), 4.30 (d, J = 10.8 Hz, 2H), 3.76 -3.68 (m, 4H), 3.28 (t, J = 9.9 Hz, 1H), 3.04 – 2.75 (m, 4H), 2.59 (q, J = 6.8 Hz, 1H), 2.49 (s, 3H), 1.99 ( s, 2H), 1.86 (d, J = 8.4 Hz, 1H), 1.43 – 1.25 (m, 2H). ESI MS [M+H] ⁺ for C ₃₁ H ₃₂ N ₇ O, calculated 518.3, found 518.3. Example 12 : N , N - dimethyl -4'-{5-[(7 S )-7-{3- oxa -6- azabicyclo [3.1.1] hept -6- yl }-6, 7,8,9- tetrahydro -5H - benzo [ 7] annen -2- yl ] -2H - pyrazolo [3,4- b ] pyridin -3- yl }-[1,1' -Biphenyl ]-2 - methamide

Step a : 1,4-dibromobenzene (1.52 g, 6.44 mmol), K ₂ CO ₃ (1.76 g, 12.8 mmol) and PdCl ₂ (dppf) (234 mg, 0.324 mmol) were added with degassed dioxane (16 mL) and degassed water (16 mL). The reaction mixture was stirred at 70°C for 4 hours, cooled to rt, _concentrated , diluted with _CH2Cl2 (25 mL), dried over _MgSO4 , and concentrated. The crude material was purified by silica gel chromatography (20% gradient of hexane:EtOAc 0) to afford the desired product (700 mg, 35%) as a colorless liquid.

Step bf : Prepare the title compound in a manner similar to Example 2, Step bf. ¹ H NMR (400 MHz, chloroform- d ) δ 11.30 (brs, 1H), 8.83 (d, J = 2.0 Hz, 1H), 8.50 (d, J = 2.1 Hz, 1H), 8.15 – 7.92 (m, 2H ), 7.70 – 7.52 (m, 2H), 7.50 – 7.45 (m, 1H), 7.43 (dd, J = 2.8, 1.5 Hz, 1H), 7.41 – 7.35 (m, 1H), 7.24 (s, 4H), 4.30 (d, J = 10.7 Hz, 2H), 3.73 (d, J = 10.8 Hz, 2H), 3.66 (d, J = 6.1 Hz, 2H), 3.27 (t, J = 9.7 Hz, 1H), 3.06- 2.95 (m, 2H), 2.89 (s, 3H), 2.48 – 2.47 (s, 3H), 2.47 (s, 2H), 2.03 – 1.88 (m, 2H), 1.84 (d, J = 8.3 Hz, 1H) , 1.44 – 1.19 (m, 2H), 0.89 – 0.75 (m, 1H). ESI MS [M+H] ⁺ for C ₃₇ H ₃₈ N ₅ O ₂ , calculated 584.3, found 584.4. Example 13 : 6-[(7 S )-2-{3-[4-(1- methyl -1 H -1,2,3- triazol -5- yl ) phenyl ]-1 H -pyrazole And [3,4- b ] pyridin -5- yl }-6,7,8,9 - tetrahydro -5 H -benzo [7] annen -7- yl ]-3- oxa -6- nitrogen Heterobicyclo [3.1.1] heptane

Step a : To 1,4-dibromobenzene (944 mg, 4.00 mmol), 1-methyl-5-(4,4,5,5-tetramethyl-1,3) at room temperature under nitrogen ,2-Dioxaboran-2-yl)-1 H -1,2,3-triazole (836 mg, 4.00 mmol), PdCl ₂ (dppf) (293 mg, 0.400 mmol) and K ₂ CO ₃ Degassed dioxane (16 mL) and degassed water (4 mL) were added to the mixture. The reaction mixture was stirred at 90°C for 14 hours, cooled, diluted _{with CH2Cl2} (200 mL), dried over _Na2SO4 , and _concentrated . The crude material was purified by silica gel chromatography (Hexane:EtOAc 0 to 100% gradient) to afford the desired product as a pale yellow oil (390 mg, 41%).

Step bf : Prepare the title compound in a manner similar to Example 2, Step bf. ¹ H NMR (400 MHz, DMSO- d ₆ , citrate) δ 14.03 (s, 1H), 8.91 (d, J = 2.0 Hz, 1H), 8.75 (d, J = 2.0 Hz, 1H), 8.29 ( d, J = 8.3 Hz, 2H), 8.02 (s, 1H), 7.80 (d, J = 8.3 Hz, 2H), 7.69 (s, 1H), 7.62 (d, J = 7.6 Hz, 1H), 7.31 ( d, J = 7.8 Hz, 1H), 4.40 – 4.19 (m, 3H), 4.16 (s, 3H), 4.01 – 3.79 (m, 2H), 3.76 – 3.59 (m, 1H), 3.51 – 3.16 (m, 3H), 3.06 – 2.83 (m, 4H), 2.62 (d, J = 15.2 Hz, 2H), 2.54 (d, J = 15.3 Hz, 2H), 2.21 – 1.93 (m, 2H), 1.27 – 1.13 (m , 2H). ESI MS [M+H] ⁺ for C ₃₁ H ₃₂ N ₇ O, calculated 518.3, found 518.3. Example 14 : 6-[( 7S )-2-{3-[4-(2,5- dimethyl - 2H -1,2,3- triazol -4- yl ) phenyl ] -1H -Pyrazolo [3,4- b ] pyridin -5- yl }-6,7,8,9 - tetrahydro - 5 H -benzo [7] annen -7- yl ]-3 - oxa- 6- Azabicyclo [3.1.1] heptane

Step a : To a solution of 4-methylbenzenesulfonylhydrazine (16.4 g, 88.2 mmol) in MeOH (88 mL) was added 4′-bromopropiophenone (18.8 g, 88.2 mmol) in one portion at room temperature. The reaction mixture was stirred at room temperature for 30 minutes and concentrated to give the desired product as a white solid (33.5 g, 99%).

Step b : To a mixture of the product from step a (7.63 g, 20.0 mmol), sodium azide (1.56 g, 24.0 mmol) and DMSO (100 mL) was added iodine (5.08 g, 20.0 mmol) at room temperature. . The mixture was stirred at room temperature for 5 minutes and methanesulfonic acid (1.30 mL, 20.0 mmol) was added. The reaction mixture was stirred at 100°C for 4 hours and cooled. _K2CO3 (13.8 g, 100 mmol) was added to the _mixture , followed by methyl iodide (2.49 mL, 40.0 mmol). The reaction mixture was stirred at room temperature for 2 h, diluted with EtOAc (1.0 L), washed with water (1 x 1.0 L), washed with 3:2 water:brine (2 x 1.0 L), and _dried over _Na2SO4 , and concentrated. The crude material was purified by silica gel chromatography (Hexane:EtOAc 0 to 100% gradient) to afford the desired product as a pale yellow oil (439 mg, 9%).

Step cg : Prepare the title compound in a similar manner to Example 2, Step bf. ¹ H NMR (400 MHz, DMSO- d ₆ , citrate) δ 13.93 (s, 1H), 8.89 (d, J = 2.0 Hz, 1H), 8.74 (d, J = 2.0 Hz, 1H), 8.23 ( d, J = 8.3 Hz, 2H), 7.88 (d, J = 8.3 Hz, 2H), 7.68 (s, 1H), 7.62 (d, J = 7.7 Hz, 1H), 7.31 (d, J = 7.8 Hz, 1H), 4.29 (d, J = 12.1 Hz, 2H), 4.23 – 4.07 (m, 1H), 4.01 (s, 3H), 3.97 – 3.79 (m, 2H), 3.72 – 3.54 (m, 1H), 3.49 – 3.20 (m, 3H), 3.07 – 2.83 (m, 4H), 2.61 (d, J = 15.2 Hz, 2H), 2.53 (s, 3H), 2.53 (d, J = 15.9 Hz, 2H), 2.20 – 1.91 (m, 2H), 1.28 – 1.11 (m, 2H). ESI MS [M+H] ⁺ for C ₃₂ H ₃₄ N ₇ O, calculated 532.3, found 532.4. Example 15 : 3-(2- methoxyethyl )-7-{3-[4-(3- methylpyridin -2- yl ) phenyl ] -1H - pyrazolo [3,4- b ] pyridin -5- yl }-2,3,4,5- tetrahydro - 1H -3- benzoazepine

Step a : To 7-bromo-2,3,4,5-tetrahydro- 1H -3-benzoazepine (565 mg, 2.50 mmol), K ₂ CO ₃ (691 mg, 5.00 mmol) at room temperature ) and DMF (13 mL), 2-bromoethyl methyl ether (235 µL, 2.50 mmol) was added. The reaction mixture was stirred at 70 °C for 3 h and at 80 °C for 12 h, cooled, diluted with EtOAc (125 mL), washed with 0.2 M NaOH _(aq) (4 x 100 mL), and _dried over _Na2SO4 , and concentrated. The crude material was purified by C18 reverse phase chromatography ((water:ACN) + 1% TFA 5 to 35% gradient) before neutralization with saturated NaHCO _{3 (aq)} and partial concentration to remove ACN. The mixture was diluted with EtOAc ₍ 200 mL), washed with 0.2 M NaOH _(aq) (2 x 200 mL), dried over _Na2SO4 , and concentrated to give the desired product as a pale yellow oil (342 mg, 48%).

Step bc : Prepare the title compound in a similar manner to Example 2, steps e and f. ¹ H NMR (400 MHz, DMSO- d ₆ , citrate) δ 13.97 (s, 1H), 8.89 (d, J = 2.0 Hz, 1H), 8.74 (d, J = 2.1 Hz, 1H), 8.53 ( dd, J = 4.8, 1.0 Hz, 1H), 8.21 (d, J = 8.4 Hz, 2H), 7.79 – 7.69 (m, 4H), 7.66 (dd, J = 7.7, 2.0 Hz, 1H), 7.34 (d , J = 7.7 Hz, 1H), 7.33 (d, J = 7.7 Hz, 1H), 3.61 (t, J = 5.2 Hz, 2H), 3.44 – 3.26 (m, 2H), 3.31 (s, 3H), 3.20 – 3.00 (m, 8H), 2.64 (d, J = 15.2 Hz, 2H), 2.55 (d, J = 15.2 Hz, 2H), 2.42 (s, 3H). ESI MS [M+H] ⁺ for C ₃₁ H ₃₂ N ₅ O, calculated 490.3, found 490.3. Example 16 : 3- methyl -2-(4-{5-[(7 S )-7-{3- oxa -6- azabicyclo [3.1.1] hept -6- yl }-6,7 ,8,9- tetrahydro -5 H -benzo [7] annen -2- yl ]-1 H -pyrrolo [2,3- b ] pyridin -3- yl } phenyl ) pyridin -1- ium -1- alkoxide

Step a : To a solution of the product from Example 1, step d (504 mg, 1.00 mmol) in CH ₂ Cl ₂ (5.0 mL) was added m -CPBA (230 mg, 1.00 mmol, 75 wt%) at room temperature. in water). The reaction mixture was stirred at room temperature for 14 hours and additional m -CPBA (115 mg, 0.500 mmol, 75 wt% in water) was added. The reaction mixture was stirred at room temperature for 5 hours and concentrated. The crude material was purified by silica gel chromatography (CH ₂ Cl ₂ :MeOH 0 to 10% gradient) to afford the desired product as a light brown solid (350 mg, 67%).

Step b : The product from Example 1, Step a (64 mg, 0.20 mmol), _B2pin2 (51 mg, 0.20 mmol), _PdCl2 (dppf) (7 mg _, 0.01 To a mixture of KOAc (39 mg, 0.40 mmol) and KOAc (39 mg, 0.40 mmol), degassed dioxane (1.0 mL) was added. The reaction mixture was stirred at 100°C for 14 h, cooled, diluted with EtOAc (10 mL), filtered through celite, and concentrated to give the desired product, which was used as crude in step c.

Step cd : Prepare the title compound in a similar manner to Example 1, steps f and g. ¹ H NMR (400 MHz, DMSO- d ₆ , citrate) δ 12.08 (d, J = 2.7 Hz, 1H), 8.58 (d, J = 2.0 Hz, 1H), 8.47 (d, J = 2.1 Hz, 1H), 8.22 (t, J = 3.9 Hz, 1H), 8.02 (d, J = 2.6 Hz, 1H), 7.91 (d, J = 8.3 Hz, 2H), 7.64 – 7.58 (m, 1H), 7.54 ( d, J = 7.6 Hz, 1H), 7.42 (d, J = 8.3 Hz, 2H), 7.34 (d, J = 3.9 Hz, 2H), 7.31 – 7.24 (m, 1H), 4.37 – 4.06 (m, 3H ), 4.00 – 3.77 (m, 2H), 3.68 – 3.49 (m, 1H), 3.46 – 3.24 (m, 3H), 3.05 – 2.80 (m, 4H), 2.61 (d, J = 15.2 Hz, 2H), 2.53 (d, J = 13.5 Hz, 2H), 2.13 (s, 3H), 2.11 – 1.88 (m, 2H), 1.41 – 1.09 (m, 2H). ESI MS [M+H] ⁺ for C ₃₅ H ₃₅ N ₄ O ₂ , calculated 543.3, found 543.3. Example 17 : 6-[( 7S )-3-[3-[6-(3- methylpyridin -2- yl ) pyridazin -3- yl ] -1H - pyrazolo [3,4- b ] pyridin -5- yl ]-6,7,8,9 - tetrahydro - 5H - benzo [7] annen -7- yl ]-3- oxa -6- azabicyclo [3.1.1] Heptane

Step a : To 3-methyl-2-(tributylstannyl)pyridine (1.91 g, 5.00 mmol), 3,6-dibromopyridazine (1.19 g, 5.00 mmol), CuI (190 mg, 0.997 mmol) Dioxane (25 mL) was added to a mixture of Pd(PPh ₃ ) ₄ (578 mg, 0.501 mmol). The mixture was purged with nitrogen for 10 minutes, stirred at 100°C for 3.5 hours, cooled, diluted with EtOAc, filtered through celite, and concentrated. The crude material was purified by silica gel chromatography (Hexane:EtOAc 0 to 100% gradient) to afford the desired product (590 mg, 47%).

Step be : Prepare the title compound in a similar manner to Example 9, Step dg. ¹ H NMR (400 MHz, chloroform- d ) δ 11.27 (s, 1H), 9.32 (d, J = 2.2 Hz, 1H), 8.89 (d, J = 2.2 Hz, 1H), 8.65 – 8.58 (m, 1H ), 8.53 (d, J = 8.9 Hz, 1H), 8.23 (d, J = 8.8 Hz, 1H), 7.76 – 7.68 (m, 1H), 7.51 – 7.43 (m, 2H), 7.37 – 7.20 (m, 2H), 4.33 (d, J = 10.7 Hz, 2H), 3.76 (m, 2H), 3.67 (m, 2H), 3.28 (m, 1H), 2.99 (td, J = 23.8, 23.0, 14.5 Hz, 2H ), 2.91 – 2.79 (m, 2H), 2.73 (s, 3H), 1.97 (m, 2H), 1.88 (m, 1H), 1.39 (m, 2H), 1.26 (m, 1H). ESI MS [M+H] ⁺ for C ₃₂ H ₃₂ N ₇ O, calculated 530.3, found 530.3. Example 18 : 3-[(7 S )-7- methyl -7-[(2 R )-2- methylpyrrolidin -1- yl ]-5,6,8,9- tetrahydrobenzo [7 ] annen -3- yl ]-5-[4-(3- methylpyridin -2- yl ) phenyl ]-7 H -pyrrolo [2,3- c ] pyridazine

Step a : Combine 2-bromo-5,6,8,9-tetrahydro-benzocyclohepten-7-one (23.9 g, 100 mmol), ( R )-2-methylpyrrolidine (9.06 mL , 105 mmol), 1,2,3-triazole (7.60 g, 110 mmol) and toluene (100 mL) in a flask equipped with a Dean-Stark water trap and heated to reflux for 18 hours with azeotropic removal of water. The mixture was cooled and added dropwise to a mixture of MeMgBr (133 mL, 400 mmol, 3 M in _Et2O ) and THF (400 mL) at 0°C. The reaction mixture was stirred at 0°C for 1 h and at room temperature for 2 h, and was carefully quenched with water (7.2 mL). The mixture was diluted with 1 M HCl _(aq) (500 mL) and MTBE (250 mL) and stirred. The organic phase was extracted once with 1 M HCl _(aq) (500 mL). The acidic aqueous phases were combined and extracted with _CH2Cl2 (2 _x 500 mL). The combined organic phases were concentrated. Water (500 mL) was added and the solution was made alkaline by adding 2 M NaOH _(aq) (100 mL). Add MTBE (500 mL) and stir and separate the phases. The organic phase was washed with 2 M NaOH _(aq) (3 x 250 mL) and dried over _Na2SO4 to give the crude product as _a light orange solid (21.2 g, 1:1 dr by NMR).

The mixture of diastereomers was dissolved in isopropanol (424 mL) with gradual heating. Once the solids are dissolved, the solution is allowed to cool. The mixture was allowed to stand for 24 hours and the solid was collected by filtration (without washing) to give the diastereomer-enriched product (5.12 g by NMR, 24% recovery, 83:17 d.r.). The enriched material was dissolved in isopropyl alcohol (102 mL) with gradual heating. Once the solids are dissolved, the solution is allowed to cool. The mixture was allowed to stand for 24 hours and the solid was collected by filtration (without washing) to give the desired product as a white solid (3.60 g by NMR, 70% recovery, ≥ 95:5 d.r.).

Chiral HPLC can also be used (YMC Amylose-SA; MeOH/DEA 100/0.1 v/v; 0.5 mL/min; UV 227 nm; 10.7 minutes (desired isomer), 12.2 minutes (other isomers)) Resolving non-mirror isomeric mixtures.

Step b : Add 3-chloro-5-iodo- 7H -pyrrolo[2,3- c ]pyridazine (1.40 g, 5.01 mmol), Cs ₂ CO ₃ (3.26 g, 10.0 mmol) and DMF at rt. (7 mL) was added SEMCl (1.33 mL, 7.51 mmol). The reaction mixture was stirred for 16 hours, diluted with EtOAc (70 mL), washed with water (3 _x 70 mL), washed with brine (70 mL), dried over _Na2SO4 , and concentrated. The crude material was purified by silica gel chromatography (Hexane:EtOAc 0 to 50% gradient) to give the desired product (1.44 g, 70%).

Step c : Prepare the desired product in a similar manner to Example 1, Step d.

Step de : Prepare the desired product in a similar manner to Example 16, step bc.

Step f : To a solution of _the product of step e (129 mg, 0.207 mmol) in _CH2Cl2 (1 mL) was added TFA (1 mL). The reaction mixture was stirred at rt for 2 hours and concentrated. To the residue was added _NH3 (2 mL, 7 M solution in MeOH). The reaction mixture was stirred at rt for 16 hours and concentrated. The crude material was purified by C18 reverse phase chromatography ((water:ACN) + 1% TFA 20 to 80% gradient) to afford the desired product as a pale yellow oil (10 mg, 9%). ¹ H NMR (400 MHz, chloroform- d ) δ 12.07 (s, 1H), 8.63 – 8.56 (m, 1H), 8.37 (s, 1H), 7.94 (s, 1H), 7.91 – 7.85 (m, 1H) , 7.83 – 7.72 (m, 3H), 7.74 – 7.59 (m, 3H), 7.30 – 7.18 (m, 2H), 3.41 (br s, 1H), 3.29 – 3.22 (m, 2H), 2.93 (t, J = 7.7 Hz, 1H), 2.68 (m, 2H), 2.55 (m, 1H), 2.46 (s, 3H), 1.90 (m, 3H), 1.72 (m, 3H), 1.47 (m, 2H), 1.08 (d, J = 6.3 Hz, 3H), 1.00 (s, 3H). ESI MS [M+H] ⁺ for C ₃₅ H ₃₈ N ₅ , calculated 528.3, found 528.3. Example 19 : 3- methyl -2-(4-{5-[6-( pyrrolidin -1- yl )-5,6,7,8- tetralin -2- yl ] -1H - pyrazole And [3,4- b ] pyridin -3- yl } phenyl ) pyridine

Step a : To a mixture of 6-bromo-3,4-dihydro-2(1 h )-naphthalenone (440 mg, 1.95 mmol), pyrrolidine (0.16 ml, 2.0 mmol) and dce (9.8 ml) was added acoh (0.11 ml, 2.0 mmol), followed by nabh(oac) ₃ (820 mg, 3.90 mmol). The reaction mixture was stirred at room temperature for 20 hours, carefully quenched with water and then with saturated Nahco _{3 ( aq )} . The phases were separated and the organic phase was extracted with _ch2cl2 (2 _x 15 ml). _The combined organic phases were washed with brine, dried over _na2so4 , and concentrated. The crude material was purified by silica gel chromatography (ch ₂ cl ₂ :meoh 0 to 10% gradient) to afford the desired product (376 mg, 69%) as a brown oil.

Step b : To a mixture of the product from Example 2, step c (132 mg, 0.294 mmol), _B2pin2 (97 mg, 0.83 mmol) and _KOAc (37 mg, 0.83 mmol) was added dioxane (2.9 mL ). The suspension was degassed with nitrogen for 5 minutes and _PdCl2 (dppf) (11 mg, 0.015 mmol) was added. The reaction mixture was stirred at 100°C for 16 h, cooled, diluted with EtOAc (15 mL), filtered through celite, and concentrated to give the desired product, which was used as crude in step c.

Step c : To a mixture of the product from step a (87 mg, 0.30 mmol), step b (0.294 mmol) and Na ₂ CO ₃ (62 mg, 0.59 mmol) was added dioxane (2.7 mL) and water (0.30 mL). The suspension was degassed with nitrogen for 5 minutes and _PdCl2 (dppf) (11 mg, 0.015 mmol) was added. The reaction mixture was stirred at 100°C for 16 hours, cooled, diluted _{with CH2Cl2} (15 mL), dried over _MgSO4 , and concentrated. The crude material was purified by silica gel chromatography ((CH ₂ Cl ₂ :MeOH) + 1% NH _{3 (aq , 28 wt%)} 0 to 10% gradient) to afford the desired product as a brown solid (64 mg, 38% , 2 steps).

Step d : To the mixture _of product from step c (64 mg, 0.11 mmol) and _CH2Cl2 (1.2 mL) was added TFA (1.2 mL). The reaction mixture was stirred at room temperature for 4 hours and concentrated. The crude material was purified by C18 reverse phase chromatography ((water:ACN) + 1% TFA 5 to 50% gradient) before partial concentration and addition _{of K2CO3} . _The mixture was extracted with _CH2Cl2 (3 x 10 mL). The combined organic phases were dried over _MgSO4 and concentrated to give the desired product as a white solid (17 mg, 31%). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.86 (d, J = 2.0 Hz, 1H), 8.72 (d, J = 2.1 Hz, 1H), 8.53 (dd, J = 4.8, 1.6 Hz, 1H) , 8.27 – 8.10 (m, 2H), 7.85 – 7.69 (m, 3H), 7.62 – 7.47 (m, 2H), 7.33 (dd, J = 7.7, 4.7 Hz, 1H), 7.22 (d, J = 7.8 Hz , 1H), 3.10 – 2.89 (m, 2H), 2.89 – 2.70 (m, 2H), 2.70 – 2.55 (m, 3H), 2.48 – 2.34 (m, 5H), 2.20 – 2.00 (m, 1H), 1.81 – 1.51 (m, 5H). ESI MS [M+H] ⁺ for C ₃₂ H ₃₂ N ₅ , calculated 486.3, found 486.3. Example 20 : 2,5- dimethyl -6-(4-{5-[(7 S )-7-{3- oxa -6- azabicyclo [3.1.1] hept -6- yl }- 6,7,8,9- tetrahydro -5 H -benzo [7] annen -2- yl ]-1 H -pyrrolo [2,3- b ] pyridin -3- yl } phenyl )-2 ,3- dihydropyridazin -3- one

Step a : To a mixture of 6-chloro-5-methyl-3(2H)-pyridazinone (952 mg, 6.59 mmol), K ₂ CO ₃ (1.18 g, 8.57 mmol) and DMF (13 mL) was added MeI (0.45 mL, 7.2 mmol). The reaction mixture was stirred at room temperature for 16 hours, diluted with water (30 mL), and extracted with MTBE (3 x 20 mL) and EtOAc (1 x 20 mL). The combined organic phases were washed with water (20 mL), brine (20 mL), dried over _MgSO4 , and concentrated. The crude material was purified by silica gel chromatography (Hexane:EtOAc 0 to 100% gradient) to afford the desired product as a white solid (816 mg, 78%).

Step b : To a mixture of the product from step a (816 mg, 5.15 mmol), (4-chlorophenyl)boronic acid (671 mg, 4.29 mmol) and Na ₂ CO ₃ (1.19 g, 8.58 mmol) was added dioxin alkane (17.2 mL) and water (4.3 mL). The suspension was degassed with nitrogen for 10 minutes and _PdCl2 (dppf) (157 mg, 0.215 mmol) was added. The reaction mixture was stirred at 80 °C for 16 h, cooled, and diluted with EtOAc (20 mL). The organic phase was dried over _MgSO4 and concentrated. The crude material was purified by silica gel chromatography (Hexane:EtOAc 0 to 50% gradient) to afford the desired product as a pale yellow solid (1.09 g, 90%).

Step cg : Prepare the title compound in a similar manner to Example 1, Step cg. ¹ H NMR (400 MHz, chloroform- d ) δ 9.71 (s, 1H), 8.62 (s, 1H), 8.40 (s, 1H), 7.78 (dt, J = 8.2, 1.6 Hz, 2H), 7.65 – 7.57 (m, 1H), 7.53 (dt, J = 8.2, 1.6 Hz, 2H), 7.44 – 7.33 (m, 2H), 7.23 (d, J = 8.1 Hz, 1H), 6.86 (d, J = 1.4 Hz, 1H), 4.31 (d, J = 10.7 Hz, 2H), 3.85 (s, 3H), 3.74 (d, J = 10.7 Hz, 2H), 3.65 (d, J = 6.1 Hz, 2H), 3.26 (t, J = 9.8 Hz, 1H), 2.99 (td, J = 15.1, 8.5 Hz, 2H), 2.86 (q, J = 13.2 Hz, 2H), 2.56 (q, J = 8.1, 7.6 Hz, 1H), 2.26 ( d, J = 1.3 Hz, 3H), 2.03 – 1.89 (m, 2H), 1.85 (d, J = 8.2 Hz, 1H), 1.34 (p, J = 10.6 Hz, 2H). ESI MS [M+H] ⁺ for C ₃₅ H ₃₆ N ₅ O ₂ , calculated 558.3, found 558.3. Example 21 : 2- Methyl -2-[2-[4-[5-[(7 S )-7-(3- oxa- 6- azabicyclo [3.1.1] hept -6- yl )- 6,7,8,9- tetrahydro -5 H -benzo [ 7] annen -3- yl ]-1 H -pyrrolo [2,3- b ] pyridin - 3- yl ] phenyl ] pyridine- 3- yl ] propionitrile

Step a : Combine 2-chloro-3-pyridineacetonitrile (5.0 g, 33 mmol), 4-chlorophenylboronic acid (7.7 g, 49 mmol), 2 M Na ₂ CO _3(aq) (49.2 mL, 98.3 mmol) The mixture with dioxane (164 mL) was purged with nitrogen for ten minutes before PdCl ₂ (dppf) (2.4 g, 3.3 mmol) was added. The resulting solution was heated to 90°C. The reaction mixture was stirred at 90°C for 36 hours, cooled, filtered through celite to remove solids, and concentrated. The crude material was purified by silica gel chromatography (Hexane:EtOAc 0 to 100% gradient) to give the desired product.

Step b : Add a mixture of the product from step a (1.14 g, 4.98 mmol), methyl iodide (1.09 mL, 17.5 mmol) and THF (8.5 mL) dropwise to sodium hydride (0.60 g, 15 mmol, 60% w /w in mineral oil) and THF (8.5 mL) in a reflux mixture. The resulting mixture was heated to reflux for three hours. The reaction was cooled to room temperature and carefully quenched with saturated _{NH4Cl (aq)} . The reaction was extracted with EtOAc and the organics were dried over _MgSO4 and concentrated. The material was used directly in the next step without further purification.

Step cg : Prepare the title compound in a similar manner to Example 1, Step cg. ¹ H NMR (400 MHz, chloroform- d ) δ 9.56 (s, 1H), 8.64 (dd, J = 4.7, 1.6 Hz, 1H), 8.58 (d, J = 8.58 Hz, 1H), 8.40 (d, J = 8.40 Hz, 1H), 8.01 (dd, = 8.1, 1.6 Hz, 1H), 7.76-7.73 (m, 2H), 7.57 (d, J = 2.2 Hz, 1H), 7.51-7.48 (m, 2H), 7.39-7.34 (m, 3H), 7.21-7.19 (m, 1H), 4.29 (d, J = 10.7 Hz, 2H), 3.72 (d, J = 10.7 Hz, 2H), 3.64 (d, J = 6.1 Hz , 2H), 3.26-3.21 (m, 1H), 3.02-2.77 (m, 4H), 2.54 (dd, J = 13.4, 7.1 Hz, 1H), 1.93 (s, 2H), 1.83 (d, J = 8.3 Hz, 1H) 1.69 (s, 6H), 1.34-1.25 (m, 2H). ESI MS [M+H] ⁺ for C ₃₈ H ₃₈ N ₅ O, calculated 580.3, found 580.3. Example 22 : 1-[2-[4-[5-[(7 S )-7-(3- oxa -6- azabicyclo [3.1.1] hept -6- yl )-6,7,8 ,9- tetrahydro - 5H - benzo [7] annen - 3- yl ] -1H - pyrrolo [2,3- b ] pyridin -3- yl ] phenyl ] pyridin -3- yl ] ring Butan -1- ol

Step a : Combine 2,3-dibromopyridine (11.8 g, 49.8 mmol), 4-chlorophenylboronic acid (8.21 g, 52.5 mmol), triphenylphosphine (1.31 g, 5.00 mmol), K ₂ CO ₃ ( A mixture of 13.8 g, 100 mmol) and a 2:1 ACN:water (375 mL) was purged with nitrogen for ten minutes before adding Pd(OAc) ₂ (561 mg, 2.50 mmol). The reaction was heated to 50°C for four hours, cooled, filtered through celite, concentrated, and purified by silica gel chromatography (CH ₂ Cl ₂ :EtOAc 0 to 50% gradient) to give the desired product.

Step b : A mixture of product from step a (999 mg, 3.72 mmol) and THF (11.2 mL) was cooled to -78°C. n -BuLi (1.63 mL, 4.08 mmol, 2.5 M in hexane) was added dropwise and the reaction was stirred at -78 °C for 90 min. Cyclobutanone (822 µL, 11.2 mmol) was added slowly and the mixture was allowed to warm to room temperature slowly over two hours. The reaction was quenched with saturated NaHCO _{3 (aq)} , extracted with EtOAc, and dried over Na ₂ SO ₄ . The crude material was purified by silica gel chromatography (CH ₂ Cl ₂ :EtOAc 0 to 50% gradient) to give the desired product.

Step cg : Prepare the title compound in a similar manner to Example 1, Step cg. ¹ H NMR (400 MHz, chloroform- d ) δ 9.97 (s, 1H), 8.62 (dd, J = 4.7, 1.7 Hz, 1H), 8.54 (d, J = 2.0 Hz, 1H), 8.35 (d, J = 2.0 Hz, 1H), 7.75-7.66 (m, 5H), 7.50 (s, 1H), 7.36-7.33 (m, 2H), 7.28 (dd, J = 7.8, 4.7 Hz, 1H), 7.18-7.16 ( m, 1H), 4.36-4.29 (m, 2H), 3.98-3.82 (m, 4H), 3.37-3.30 (m, 1H), 3.02-2.77 (m, 6H), 2.40-2.30 (m, 2H), 2.12-2.09 (m, 3H), 1.98-1.88 (m, 3H), 1.66-1.57 (m, 3H). ESI MS [M+H] ⁺ for C ₃₈ H ₃₉ N ₄ O ₂ , calculated 583.3, found 583.3. Example 23 : 6-[(7 S )-2-{3-[4-(1,3- dimethyl -1 H -1,2,4 -triazol -5- yl ) phenyl ]-1 H -Pyrazolo [3,4- b ] pyridin -5- yl }-6,7,8,9 - tetrahydro - 5 H -benzo [7] annen -7- yl ]-3 - oxa- 6- Azabicyclo [3.1.1] heptane

Step a : To a solution of 4-bromobenzoic acid (1.01 g, 5.02 mmol) in DMF (18 mL) was added acetamidine hydrochloride (709 mg, 7.50 mmol), HATU (2.09 g, 5.50 mmol) and DIPEA (2.61 mL, 15.0 mmol). The reaction mixture was stirred at room temperature for 2 hours, then methylhydrazine (0.40 mL, 7.5 mmol) and acetic acid (2.86 mL, 50.0 mmol) were added. The reaction mixture was stirred at 80 °C for 3 h, cooled to room temperature, diluted with EtOAc (200 mL), washed with saturated NaHCO3 _{( aq)} (1 x 200 mL), dried over _Na2SO4 , and concentrated. The crude material was purified by silica gel chromatography (Hexane:EtOAc 0 to 100% gradient) to afford the desired product as a white solid (895 mg, 71%).

Step b : Prepare the desired product in a similar manner to Example 1, Step e.

Step cf : Prepare the desired product in a similar manner to Example 2. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 13.99 (s, 1H), 8.85 (d, J = 2.1 Hz, 1H), 8.71 (d, J = 2.1 Hz, 1H), 8.31 – 8.23 (m, 2H), 7.93 – 7.85 (m, 2H), 7.59 (d, J = 2.0 Hz, 1H), 7.53 (dd, J = 7.5, 2.0 Hz, 1H), 7.23 (d, J = 7.8 Hz, 1H), 4.13 (d, J = 10.6 Hz, 2H), 3.93 (s, 3H), 3.53 (dd, J = 18.8, 8.3 Hz, 4H), 3.20 – 3.09 (m, 1H), 3.05 – 2.85 (m, 2H) , 2.77 (q, J = 14.7, 14.2 Hz, 2H), 2.37 – 2.29 (m, 1H), 2.26 (s, 3H), 1.90 – 1.77 (m, 2H), 1.65 (d, J = 7.8 Hz, 1H ), 1.25 – 1.04 (m, 2H). ESI MS [M+H] ⁺ for C ₃₂ H ₃₄ N ₇ O, calculated 532.3, found 532.3. Example 24 : 3- Cyclopentyl -7-{3-[4-(3- methylpyridin -2- yl ) phenyl ] -1H - pyrazolo [3,4- b ] pyridin -5- yl }-2,3,4,5- tetrahydro - 1H -3- benzoazepine

Step a : To 7-bromo-2,3,4,5-tetrahydro-1H-3-benzoazepine hydrochloride (272 mg, 1.04 mmol), cyclopentanone (0.11 mL, 1.3 mmol) and DCE (5.2 mL) was added AcOH (60 μL, 1.0 mmol), followed by NaBH(OAc) ₃ (331 mg, 1.56 mmol). The reaction mixture was stirred at room temperature for 17 h and carefully quenched with saturated NaHCO _{3 (aq)} . The layers were separated and the aqueous layer was extracted with _CH2Cl2 (2 _x 10 mL). The combined organic layers were washed with brine, dried over _MgSO4 , and concentrated to give the desired product as a colorless oil (293 mg, 96%).

Step b : To a mixture of product from step a (111 mg, 0.377 mmol), _B2pin2 (129 mg, 0.490 mmol) and KOAc ( ₄₈ mg, 0.49 mmol) was added dioxane (3.8 mL). The suspension was degassed with nitrogen for 10 minutes and _PdCl2 (dppf) (14 mg, 0.019 mmol) was added. The reaction mixture was stirred at 90°C for 3 h, cooled, diluted with EtOAc (15 mL), filtered through celite, and concentrated to give the desired product, which was used as crude in step c.

Step cd : The desired product is prepared in a manner similar to Example 2, Steps e and f using the bromoazaindazole intermediate formed from Example 2, Step c. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 13.94 (s, 1H), 8.87 (d, J = 2.1 Hz, 1H), 8.73 (d, J = 2.1 Hz, 1H), 8.53 (dd, J = 5.0, 1.6 Hz, 1H), 8.24 – 8.17 (m, 2H), 7.80 – 7.70 (m, 3H), 7.65 – 7.53 (m, 2H), 7.33 (dd, J = 7.7, 4.7 Hz, 1H), 7.25 (d, J = 7.7 Hz, 1H), 3.03 – 2.94 (m, 2H), 2.94 – 2.88 (m, 2H), 2.88 – 2.80 (m, 1H), 2.74 – 2.54 (m, 4H), 2.42 (s , 3H), 1.88 – 1.70 (m, 2H), 1.67 – 1.56 (m, 2H), 1.56 – 1.44 (m, 2H), 1.44 – 1.33 (m, 2H), 1.31 – 1.21 (m, 1H). ESI MS [M+H] ⁺ for C ₃₃ H ₃₄ N ₅ , calculated 500.3, found 500.3. Example 25 : 6-[(7 S )-2-{3-[5-(3- methylpyridin -2- yl )-1,3,4- oxadiazol -2- yl ]-1 H -pyridin Azolo [3,4- b ] pyridin -5- yl }-6,7,8,9 - tetrahydro -5 H -benzo [7] annen -7- yl ]-3- oxa -6- Azabicyclo [3.1.1] heptane

Step a : To a mixture of 5-bromo- 1H -pyrazolo[3,4- b ]pyridine-3-carboxylic acid (1.21 g, 5.00 mmol) and MeOH (12.5 mL) was added sulfuric acid (0.5 mL, 98 wt%). The reaction mixture was stirred at 75°C for 18 hours, cooled, and concentrated to give the desired product, which was used as crude in step b.

Step b : To a mixture of the product from step a (5.00 mmol), camphorsulfonic acid (117 mg, 0.504 mmol) and THF (12.5 mL) was added 3,4-dihydro- 2H -piran at room temperature. (0.92 mL, 10 mmol). The reaction mixture was stirred at 65°C for 4 hours, cooled, and quenched with NH3 _(aq) (10 mL, 28 wt%) and concentrated. The crude material was purified by silica gel chromatography (Hexane:EtOAc 0 to 50% gradient) to afford the desired product as a white solid (1.20 g, 70%, two steps).

Step c : To a mixture of the product from step b (1.20 g, 3.52 mmol) in 1:1 THF/MeOH (10 mL) was added hydrazine monohydrate (0.86 mL, 18 mmol). The mixture was stirred at 75°C for 18 hours, cooled, and concentrated. The crude material was purified by silica gel chromatography (Hexane:EtOAc 0 to 50% gradient) to afford the desired product as a white solid (1.16 g, 97%).

Step d : To a mixture of the product from step c (579 mg, 1.70 mmol) and DMF (5.1 mL) was added 3-methylpyridine-2-carboxylic acid (280 mg, 2.04 mmol), HATU (2.09 g, 2.55 mmol) and triethylamine (0.47 mL, 3.4 mmol). The mixture was stirred at room temperature for 18 h, diluted with EtOAc (100 mL), washed with saturated NaHCO3 _{( aq)} (1 x 20 mL), dried over _Na2SO4 , and concentrated. The crude material was purified by silica gel chromatography (Hexane:EtOAc 0 to 100% gradient) to afford the desired product as a colorless oil (711 mg, 91%).

Step e : To a mixture of the product from step d (711 mg, 1.55 mmol) and CH ₂ Cl ₂ (20 mL) was added triethylamine (1.08 mL, 7.75 mmol), triphenylphosphine (509 mg, 1.94 mmol) ) and carbon tetrachloride (0.19 mL, 2.0 mmol). The reaction mixture was stirred at room temperature for 4 h, diluted with EtOAc (100 mL), washed with saturated NaHCO3 _{( aq)} (1 x 20 mL), dried over _Na2SO4 , and concentrated. The crude material was purified by silica gel chromatography (Hexane:EtOAc 0 to 100% gradient) to afford the desired product as a colorless oil (499 mg, 73%).

Step fh : Prepare the desired product in a similar manner to Example 2, Step df. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.96 (s, 1H), 8.71 – 8.64 (m, 2H), 7.94 (dd, J = 7.9, 1.6 Hz, 1H), 7.58 – 7.54 (m, 2H ), 7.50 (dd, J = 7.7, 2.0 Hz, 1H), 7.26 (d, J = 7.8 Hz, 1H), 4.13 (d, J = 10.6 Hz, 2H), 3.59 – 3.49 (m, 4H), 3.20 – 2.10 (m, 1H), 3.06 – 2.86 (m, 2H), 2.85 – 2.71 (m, 5H), 2.38 – 2.28 (m, 1H), 1.91 – 1.78 (m, 2H), 1.65 (d, J = 7.9 Hz, 1H), 1.25 – 1.04 (m, 2H). ESI MS [M+H] ⁺ for C ₃₀ H ₃₀ N ₇ O ₂ , calculated 520.3, found 520.3. Example 26 : 3- methyl -6'-{5-[(7 S )-7-{3- oxa -6- azabicyclo [3.1.1] hept -6- yl }-6,7,8 ,9- tetrahydro -5 H -benzo [7] annen -2- yl ]-1 H -pyrazolo [3,4- b ] pyridin -3- yl }-2,3'- bipyridine

Step a : 5-Bromo-2-pyridinecarboxylic acid methyl ester (648 mg, 3.00 mmol), B ₂ pin ₂ (762 mg, 3.00 mmol), PdCl ₂ (dppf) (110 mg, 0.150 mmol) and KOAc (589 mg, 6.00 mmol) was added degassed dioxane (15 mL). The reaction mixture was stirred at 100°C for 1 h, cooled, diluted with EtOAc (30 mL), filtered through celite, and concentrated to give the desired product, which was used as crude in step b.

Step b : The product from step a (assumed 3.00 mmol), 2-bromo-3-methylpyridine (774 mg, 4.50 mmol), PdCl ₂ (dppf) (110 mg, 0.150 mmol) and Na ₂ CO ₃ (636 mg, 6.00 mmol), degassed toluene (9.0 mL), ACN (6.0 mL) and water (3.0 mL) were added. The reaction mixture was stirred at 70 °C for 2 h, cooled, diluted with EtOAc (30 mL), washed with water, washed with _brine , dried over _Na2SO4 , and concentrated. The crude material was purified by silica gel chromatography (Hexane:EtOAc 0 to 100% gradient) to afford the desired product (524 mg, 76%) as a light brown solid.

Step c : To a solution of 2-fluoro-6-bromopyridine (823 µL, 8.00 mmol) in THF (16 mL) was added LDA (4.00 mL, 8.00 mmol, 2 M in ethyl) dropwise at -78 °C. benzene/THF/heptane). The reaction mixture was stirred at -78°C for 30 minutes. To the mixture was added a solution of the product from step b (913 mg, 4.00 mL) in THF (4.0 mL) at -78°C. The reaction mixture was stirred at -78°C for 1 h, quenched with saturated NH ₄ Cl _(aq) at -78°C, allowed to warm to room temperature, and diluted with EtOAc (20 mL). The organic phase was dried over _Na2SO4 , concentrated, and triturated with hexane to give the desired product as _a brown solid (872 mg, 59%).

Step d : To a mixture of the product from step c (186 mg, 0.500 mmol) in 1:1 i -PrOH:dioxane (2.5 mL) was added hydrazine monohydrate (24 µL, 0.50 mmol). The reaction mixture was stirred at room temperature for 1.5 hours. Triethylamine (87 µL, 0.60 mmol) and dioxane (2.5 mL) were added to the mixture at room temperature. The reaction mixture was stirred at room temperature for 3 hours, at 60°C for 1 hour, and diluted with water (25 mL). The precipitated solid was collected by filtration, washed with water, dried (149 mg), and recrystallized from EtOAc (5 mL) to give the desired product as an off-white solid (93 mg, 51%).

Step e : To a mixture of the product from step d (366 mg, 1.00 mmol) and THF (5.0 mL) was added potassium tertiary butoxide (106 mg, 1.10 mmol) in one portion at room temperature. The reaction mixture was stirred at room temperature for 15 minutes and 4-toluenesulfonyl chloride (191 mg, 1.00 mmol) was added in one portion. The reaction mixture was stirred at room temperature for 30 minutes and diluted with water (25 mL). The precipitated solid was collected by filtration, washed with water, and dried to give the desired product as a brown solid (458 mg, 88%).

Step fg : Prepare the title compound in a manner analogous to Example 16, steps c and d. ¹ H NMR (400 MHz, chloroform- d ) δ 11.66 (s, 1H), 9.17 (d, J = 2.1 Hz, 1H), 8.94 (dd, J = 2.3, 0.9 Hz, 1H), 8.85 (d, J = 2.2 Hz, 1H), 8.58 (ddd, J = 4.8, 1.7, 0.7 Hz, 1H), 8.31 (dd, J = 8.2, 0.9 Hz, 1H), 8.02 (dd, J = 8.2, 2.3 Hz, 1H) , 7.63 (ddd, J = 7.7, 1.7, 0.8 Hz, 1H), 7.44 (dq, J = 3.8, 2.0 Hz, 2H), 7.25 (s, 1H), 7.23 – 7.20 (m, 1H), 4.30 (d , J = 10.7 Hz, 2H), 3.73 (d, J = 10.7 Hz, 2H), 3.66 (d, J = 6.1 Hz, 1H), 3.26 (t, J = 9.6 Hz, 1H), 3.07 – 2.79 (m , 3H), 2.57 (q, J = 6.8 Hz, 1H), 2.46 (s, 3H), 1.94 (s, 2H), 1.84 (d, J = 8.3 Hz, 1H), 1.41 – 1.20 (m, 3H) , 0.89 – 0.72 (m, 1H). ESI MS [M+H] ⁺ for C ₃₃ H ₃₃ N ₆ O, calculated 529.3, found 529.3. Example 27 : 6-[( 7S )-2-{3-[1-(3- methylpyridin -2- yl ) -1H - pyrazol -4- yl ] -1H - pyrrolo [2, 3- b ] Pyridin -5- yl }-6,7,8,9 - tetrahydro - 5H - benzo [7] annen -7- yl ]-3- oxa -6- azabicyclo [3.1 .1] heptane

Step a : Combine 4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl) -1H -pyrazole (1.94 g, 10.0 mmol), 2- A mixture of fluoro-3-methylpyridine (1.11 g, 10.0 mmol), Cs ₂ CO ₃ (3.58 g, 11.0 mmol) and DMSO (10 mL) was stirred at 120 °C for 15 h, cooled, and treated with EtOAc (100 mL) Dilute, wash with 9:1 water:brine (4 _x 200 mL), dry over _Na2SO4 , and concentrate. The crude material was purified by silica gel chromatography (Hexane:EtOAc 0 to 50% gradient) to afford the desired product as a white solid (515 mg, 18%).

Step be : Prepare the title compound (citrate salt) in a similar manner to Example 1, Step dg. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.87 (d, J = 2.6 Hz, 1H), 8.84 (d, J = 0.8 Hz, 1H), 8.55 (d, J = 2.1 Hz, 1H), 8.43 (d, J = 2.1 Hz, 1H), 8.41 (dd, J = 4.5, 1.3 Hz, 1H), 8.35 (d, J = 0.8 Hz, 1H), 7.94 (d, J = 2.5 Hz, 1H), 7.91 (dd, J = 7.5, 0.9 Hz, 1H), 7.63 (s, 1H), 7.57 (d, J = 7.7 Hz, 1H), 7.40 (dd, J = 7.6, 4.7 Hz, 1H), 7.27 (d, J = 7.8 Hz, 1H), 4.39 – 4.07 (m, 3H), 4.01 – 3.79 (m, 2H), 3.73 – 3.55 (m, 1H), 3.50 – 3.17 (m, 3H), 3.07 – 2.80 (m, 4H), 2.61 (d, J = 15.2 Hz, 2H), 2.54 (s, 3H), 2.53 (d, J = 14.4 Hz, 2H), 2.21 – 1.90 (m, 2H), 1.30 – 1.11 (m, 2H ). ESI MS [M+H] ⁺ for C ₃₂ H ₃₃ N ₆ O, calculated 517.3, found 517.3. Example 28 : 6-[( 7S )-3-[3-[4-(5- fluoro -3- methylpyridin -2- yl ) phenyl ] -1H - pyrazolo [3,4- b ] pyridin -5- yl ]-6,7,8,9 - tetrahydro - 5H - benzo [7] annen -7- yl ]-3- oxa -6- azabicyclo [3.1.1] Heptane

The title compound was prepared in an analogous manner to Example 2 from appropriate starting materials. ¹ H NMR (400 MHz, chloroform- d ) δ 10.84 (s, 1H), 8.84 (d, J = 2.0 Hz, 1H), 8.51 (d, J = 2.1 Hz, 1H), 8.43 (dd, J = 2.8 , 0.6 Hz, 1H), 8.13 – 8.05 (m, 2H), 7.72 – 7.64 (m, 2H), 7.43 – 7.33 (m, 3H), 7.30 – 7.21 (m, 1H), 4.31 (d, J = 10.7 Hz, 2H), 3.74 (d, J = 10.9 Hz, 2H), 3.66 (m, 2H), 3.27 (m, 1H), 3.04 – 2.93 (m, 2H), 2.86 (q, J = 13.2 Hz, 2H ), 2.57 (m, 1H), 2.46 (t, J = 0.7 Hz, 3H), 1.98 (m, 2H), 1.85 (d, J = 8.2 Hz, 1H), 1.37 – 1.22 (m, 2H). ESI MS [M+H] ⁺ for C ₃₄ H ₃₃ FN ₅ O, calculated 546.3, found 546.3. Example 29 : 6-[( 7S )-3-[3-[4-(5- fluoro -3- methylpyridin -2- yl ) phenyl ] -1H - pyrrolo [2,3- b ] Pyridin -5- yl ]-6,7,8,9 - tetrahydro - 5H - benzo [7] annen -7- yl ]-3- oxa -6- azabicyclo [3.1.1] heptan alkyl

The title compound was prepared in an analogous manner to Example 1 from appropriate starting materials. ¹ H NMR (400 MHz, chloroform- d ) δ 8.89 (s, 1H), 8.61 (d, J = 2.0 Hz, 1H), 8.45 – 8.38 (m, 2H), 7.80 – 7.72 (m, 2H), 7.65 – 7.54 (m, 3H), 7.39 (s, 2H), 7.42 – 7.32 (m, 1H), 7.23 – 7.20 (m, 1H), 4.31 (d, J = 10.7 Hz, 2H), 3.73 (d, J = 10.7 Hz, 2H), 3.64 (d, J = 6.0 Hz, 2H), 3.25 (m, 1H), 3.01 – 2.77 (m, 4H), 2.56 (m, 1H), 2.47 (s, 3H), 1.94 (m, 2H), 1.84 (d, J = 8.2 Hz, 1H), 1.36 – 1.24 (m, 2H). ESI MS [M+H] ⁺ for C ₃₅ H ₃₄ FN ₄ O, calculated 545.3, found 545.3. Example 30 : 6-[( 7S )-3-[3-[2- methyl- 4-(3- methylpyridin -2- yl ) phenyl ] -1H - pyrazolo [3,4- b ] pyridin -5- yl ]-6,7,8,9 - tetrahydro - 5H - benzo [7] annen -7- yl ]-3- oxa -6- azabicyclo [3.1.1 ] Heptane

The title compound was prepared in an analogous manner to Example 2 from appropriate starting materials. ¹ H NMR (400 MHz, chloroform- d ) δ 11.51 (s, 1H), 8.87 (d, J = 2.1 Hz, 1H), 8.56 (ddd, J = 4.7, 1.8, 0.7 Hz, 1H), 8.20 (d , J = 2.1 Hz, 1H), 7.67 – 7.60 (m, 2H), 7.57 (dt, J = 1.8, 0.6 Hz, 1H), 7.50 (ddd, J = 7.8, 1.9, 0.7 Hz, 1H), 7.34 ( d, J = 11.8 Hz, 2H), 7.21 (dd, J = 7.8, 4.8 Hz, 2H), 4.31 (d, J = 10.8 Hz, 2H), 3.73 (dd, J = 10.6, 4.1 Hz, 2H), 3.66 (d, J = 5.8 Hz, 2H), 3.26 (t, J = 9.9 Hz, 1H), 3.05 – 2.80 (m, 4H), 2.57 (q, J = 6.8 Hz, 1H), 2.52 (s, 3H ), 2.44 (s, 3H), 1.94 (m, 2H), 1.84 (dd, J = 8.3, 3.6 Hz, 1H), 1.38 – 1.28 (m, 2H). ESI MS [M+H] ⁺ for C ₃₅ H ₃₆ N ₅ O, calculated 542.3, found 542.3. Example 31 : 1-[4-[5-[(7 S )-7-(3- oxa -6- azabicyclo [3.1.1] hept -6- yl )-6,7,8,9- Tetrahydro - 5H - benzo [7] annen -3- yl ] -1H - pyrazolo [3,4- b ] pyridin -3- yl ] phenyl ] pyridin -2- one

The title compound was prepared in an analogous manner to Example 2 from appropriate starting materials. ¹ H NMR (400 MHz, chloroform- d ) δ 11.51 (s, 1H), 8.86 (d, J = 2.1 Hz, 1H), 8.50 (d, J = 2.1 Hz, 1H), 8.16 – 8.08 (m, 2H ), 7.62 – 7.54 (m, 2H), 7.48 – 7.36 (m, 4H), 7.30 – 7.21 (m, 1H), 6.71 (ddd, J = 9.2, 1.3, 0.9 Hz, 1H), 6.30 (td, J = 6.7, 1.3 Hz, 1H), 4.33 (d, J = 10.9 Hz, 2H), 3.78 (m, 3H), 3.30 (m, 1H), 3.01 (td, J = 15.5, 7.9 Hz, 2H), 2.86 (q, J = 13.4, 13.0 Hz, 2H), 2.64 (m, 1H), 1.97 (m, 2H), 1.88 (d, J = 8.4 Hz, 1H), 1.42 (m, 2H), 1.26 (m, 1H). ESI MS [M+H] ⁺ for C ₃₃ H ₃₂ N ₅ O ₂ , calculated 530.3, found 530.2. Example 32 : ( 3S ) -N -[( 7S )-3-[3-(4- pyridin -2- ylphenyl ) -1H - pyrrolo [2,3- b ] pyridin -5- yl ]-6,7,8,9- tetrahydro - 5H - benzo [7] annen -7- yl ] oxan -3- amine .

The title compound was prepared in an analogous manner to Example 1 from appropriate starting materials. ¹ H NMR (400 MHz, chloroform- d ) δ 9.66 (s, 1H), 8.76 – 8.69 (m, 1H), 8.61 (d, J = 2.0 Hz, 1H), 8.44 (d, J = 2.1 Hz, 1H ), 8.16 – 8.08 (m, 2H), 7.84 – 7.76 (m, 4H), 7.63 (d, J = 2.3 Hz, 1H), 7.41 (dq, J = 3.5, 2.0 Hz, 2H), 7.29 – 7.19 ( m, 2H), 3.93 (dd, J = 11.0, 3.3 Hz, 1H), 3.81 (dt, J = 11.2, 4.1 Hz, 1H), 3.48 – 3.37 (m, 1H), 3.23 – 3.13 (m, 1H) , 3.01 – 2.86 (m, 3H), 2.83 (t, J = 10.3 Hz, 2H), 2.75 (d, J = 13.8 Hz, 1H), 2.11 (t, J = 12.8 Hz, 2H), 2.01 – 1.93 ( m, 1H), 1.77 – 1.56 (m, 2H), 1.35 (dq, J = 30.8, 18.0, 15.1 Hz, 4H). ESI MS [M+H] ⁺ for C ₃₄ H ₃₅ N ₄ O, calculated 515.3, found 515.3. Example 33 : (1 S ,4 S )-5-[ ( 7 S ) -3-[3-(4- pyridin -2- ylphenyl )-1 H -pyrrolo [2,3- b ] pyridine- 5- yl ]-6,7,8,9 - tetrahydro - 5H - benzo [7] annen -7- yl ]-2- oxa -5- azabicyclo [2.2.1] heptane

The title compound was prepared in an analogous manner to Example 1 from appropriate starting materials. ¹ H NMR (400 MHz, chloroform- d ) δ 9.43 (s, 1H), 8.76 – 8.69 (m, 1H), 8.61 (d, J = 2.0 Hz, 1H), 8.43 (d, J = 2.0 Hz, 1H ), 8.16 – 8.08 (m, 2H), 7.84 – 7.77 (m, 4H), 7.62 (d, J = 2.5 Hz, 1H), 7.39 (dq, J = 3.5, 2.0 Hz, 2H), 7.29 – 7.18 ( m, 2H), 4.43 (s, 1H), 4.09 (d, J = 7.7 Hz, 1H), 3.77 (s, 1H), 3.68 (dd, J = 7.5, 1.6 Hz, 1H), 3.15 (m, J = 9.7 Hz, 3H), 2.83 (s, 1H), 2.72 (m, 2H), 2.51 (d, J = 9.6 Hz, 1H), 1.98 (m, 2H), 1.90 (d, J = 9.9 Hz, 1H ), 1.78 (d, J = 9.8 Hz, 1H), 1.27 (m, J = 7.7 Hz, 1H), 0.92 – 0.81 (m, 1H). ESI MS [M+H] ⁺ for C ₃₄ H ₃₃ N ₄ O, calculated 513.3, found 513.3. Example 34 : 3-[4-(5- fluoro -3- methylpyridin -2- yl ) phenyl ]-5-[(7 S )-7- methyl -7-[(2 R )-2- Methylpyrrolidin -1- yl ]-5,6,8,9- tetrahydrobenzo [7] annen -3- yl ]-1 H -pyrrolo [2,3- b ] pyridine

The title compound was prepared in an analogous manner to Example 1 from appropriate starting materials. ¹ H NMR (400 MHz, chloroform- d ) δ 9.81 (s, 1H), 8.63 (d, J = 2.1 Hz, 1H), 8.46 – 8.39 (m, 2H), 7.81 – 7.73 (m, 2H), 7.65 – 7.57 (m, 3H), 7.42 – 7.32 (m, 3H), 7.21 (d, J = 8.2 Hz, 1H), 3.39 (br s, 1H), 3.29 – 3.20 (m, 2H), 2.92 (t, J = 7.6 Hz, 1H), 2.74 – 2.48 (m, 3H), 2.47 (s, 3H), 1.99 – 1.83 (m, 3H), 1.79 – 1.61 (m, 3H), 1.51 – 1.41 (m, 2H) , 1.08 (d, J = 6.3 Hz, 3H), 1.00 (s, 3H). ESI MS [M+H] ⁺ for C ₃₆ H ₃₈ FN ₄ , calculated value 545.3, found value 545.3. Example 35 : 6-[(7 S )-3-[3-[5-(5- fluoro -3- methylpyridin -2- yl ) pyridin -2- yl ]-1 H -pyrrolo [2,3 - b ] pyridin -5- yl ]-6,7,8,9 - tetrahydro -5 H -benzo [7] annen -7- yl ]-3- oxa -6- azabicyclo [3.1. 1] Heptane

The title compound was prepared in an analogous manner to Example 9 from appropriate starting materials. ¹ H NMR (400 MHz, chloroform- d ) δ 10.93 (s, 1H), 8.94 (d, J = 2.1 Hz, 1H), 8.84 (dd, J = 2.3, 0.8 Hz, 1H), 8.63 (d, J = 2.1 Hz, 1H), 8.44 (dd, J = 2.8, 0.7 Hz, 1H), 8.02 (d, J = 1.9 Hz, 1H), 7.91 (dd, J = 8.2, 2.3 Hz, 1H), 7.78 (dd , J = 8.2, 0.9 Hz, 1H), 7.44 (dq, J = 3.7, 2.0 Hz, 2H), 7.37 (ddd, J = 9.0, 2.8, 0.8 Hz, 1H), 7.23 (d, J = 8.2 Hz, 1H), 4.32 (d, J = 10.7 Hz, 2H), 3.71 (dd, J = 27.1, 8.4 Hz, 4H), 3.32 – 3.22 (m, 1H), 2.99 (td, J = 19.7, 17.0, 7.8 Hz , 2H), 2.86 (q, J = 13.7, 13.1 Hz, 2H), 2.59 (q, J = 6.8 Hz, 1H), 2.48 (d, J = 0.8 Hz, 3H), 1.96 (m, 2H) 1.85 ( d, J = 8.3 Hz, 1H), 1.36 (p, J = 10.4 Hz, 2H). ESI MS [M+H] ⁺ for C ₃₄ H ₃₃ FN ₅ O, calculated 546.3, found 546.3. Example 36 : 6-[( 7S )-3-[5-[4-(3- methylpyridin -2- yl ) phenyl ] -7H - pyrrolo [2,3- c ] pyridazine -3 -yl ] -6,7,8,9 - tetrahydro - 5H - benzo [7] annen -7- yl ]-3- oxa -6- azabicyclo [3.1.1] heptane

The title compound was prepared in an analogous manner to Example 18 from appropriate starting materials. ¹ H NMR (400 MHz, chloroform- d ) δ 12.27 (s, 1H), 8.65 – 8.55 (m, 1H), 8.38 (s, 1H), 7.96 – 7.90 (m, 2H), 7.87 – 7.71 (m, 3H), 7.72 – 7.58 (m, 3H), 7.31 – 7.17 (m, 2H), 4.32 (d, J = 10.6 Hz, 2H), 3.74 (d, J = 10.7 Hz, 2H), 3.67 (d, J = 6.0 Hz, 2H), 3.32 – 3.22 (m, 1H), 3.06 (dt, J = 18.8, 9.6 Hz, 1H), 2.98 (s, 1H), 2.90 (p, J = 13.9 Hz, 2H), 2.57 (q, J = 6.8 Hz, 1H), 2.45 (s, 3H), 1.96 (t, J = 10.7 Hz, 2H), 1.85 (d, J = 8.2 Hz, 1H), 1.34 (m, 2H). ESI MS [M+H] ⁺ for C ₃₄ H ₃₄ N ₅ O, calculated 528.3, found 528.3. Example 37 : 6-[(7 S )-3-[3-[5-(3- methylpyridin -2- yl ) pyrimidin -2- yl ]-1 H -pyrrolo [2,3- b ] pyridine -5- yl ]-6,7,8,9 - tetrahydro - 5H - benzo [7] annen -7- yl ]-3- oxa -6- azabicyclo [3.1.1] heptane

The title compound was prepared in an analogous manner to Example 9 from appropriate starting materials. ¹ H NMR (400 MHz, chloroform- d ) δ 10.36 (s, 1H), 9.17 (d, J = 2.2 Hz, 1H), 8.99 (s, 2H), 8.65 – 8.57 (m, 2H), 8.40 (d , J = 2.5 Hz, 1H), 7.65 (ddd, J = 7.7, 1.7, 0.8 Hz, 1H), 7.47 (dq, J = 3.4, 1.8 Hz, 2H), 7.30 – 7.20 (m, 2H), 4.32 ( d, J = 10.7 Hz, 2H), 3.74 (d, J = 10.7 Hz, 2H), 3.70 – 3.63 (m, 2H), 3.33 – 3.23 (m, 1H), 3.00 (ddd, J = 22.8, 14.3, 7.8 Hz, 2H), 2.90 (d, J = 14.8 Hz, 1H), 2.84 (d, J = 14.6 Hz, 1H), 2.57 (q, J = 6.7 Hz, 1H), 2.49 (s, 3H), 1.96 (s, 2H), 1.85 (d, J = 8.3 Hz, 1H), 1.35 (p, J = 10.5 Hz, 2H). ESI MS [M+H] ⁺ for C ₃₃ H ₃₃ N ₆ O, calculated 529.3, found 529.3. Example 38 : 6-[( 7S )-3-[3-[2-(3- methylpyridin -2- yl ) pyrimidin -5- yl ] -1H - pyrrolo [2,3- b ] pyridine -5- yl ]-6,7,8,9 - tetrahydro - 5H - benzo [7] annen -7- yl ]-3- oxa -6- azabicyclo [3.1.1] heptane

The title compound was prepared in an analogous manner to Example 17 from appropriate starting materials. ¹ H NMR (400 MHz, chloroform- d ) δ 10.55 (s, 1H), 9.25 (s, 2H), 8.72 – 8.63 (m, 2H), 8.42 (d, J = 2.0 Hz, 1H), 7.76 (d , J = 2.3 Hz, 1H), 7.68 (ddd, J = 7.7, 1.7, 0.8 Hz, 1H), 7.40 (dq, J = 4.6, 2.1 Hz, 2H), 7.32 (dd, J = 7.7, 4.7 Hz, 1H), 7.24 (t, J = 8.4 Hz, 1H), 4.32 (dd, J = 10.6, 3.2 Hz, 2H), 3.74 (d, J = 10.9 Hz, 2H), 3.66 (d, J = 6.0 Hz, 2H), 3.26 (t, J = 9.7 Hz, 1H), 3.00 (td, J = 18.5, 16.6, 7.9 Hz, 2H), 2.89 (d, J = 13.4 Hz, 1H), 2.83 (d, J = 14.1 Hz, 1H), 2.64 (s, 3H), 2.56 (q, J = 6.8 Hz, 1H), 1.96 (d, J = 11.2 Hz, 2H), 1.85 (d, J = 8.2 Hz, 1H), 1.36 ( q, J = 11.2, 10.6 Hz, 2H). ESI MS [M+H] ⁺ for C ₃₃ H ₃₃ N ₆ O, calculated 529.3, found 529.3. Example 39 : 1- methyl -6-[4-[5-[(7 S )-7-(3- oxa -6- azabicyclo [3.1.1] hept -6- yl )-6,7 ,8,9- tetrahydro - 5H - benzo [7] annen- 3 - yl ] -1H - pyrrolo [ 2,3- b ] pyridin- 3- yl ] phenyl ] pyridin -2- one

The title compound was prepared in an analogous manner to Example 1 from appropriate starting materials. ¹ H NMR (400 MHz, chloroform- d ) δ 9.61 (s, 1H), 8.62 (d, J = 2.1 Hz, 1H), 8.40 (d, J = 2.0 Hz, 1H), 7.82 – 7.74 (m, 2H ), 7.62 (d, J = 2.5 Hz, 1H), 7.49 – 7.41 (m, 2H), 7.43 – 7.33 (m, 3H), 7.29 – 7.19 (m, 1H), 6.63 (dd, J = 9.1, 1.4 Hz, 1H), 6.18 (dd, J = 6.8, 1.4 Hz, 1H), 4.31 (d, J = 10.7 Hz, 2H), 3.74 (d, J = 10.7 Hz, 2H), 3.66 (d, J = 6.0 Hz, 2H), 3.48 (s, 3H), 3.26 (t, J = 9.7 Hz, 1H), 2.99 (td, J = 14.9, 7.8 Hz, 2H), 2.86 (q, J = 13.5 Hz, 2H), 2.56 (q, J = 6.8 Hz, 1H), 1.95 (m, 2H), 1.85 (d, J = 8.3 Hz, 1H), 1.33 (m, 2H). ESI MS [M+H] ⁺ for C ₃₅ H ₃₅ N ₄ O ₂ , calculated 543.3, found 543.3. Example 40 : 6-[( 7S )-2-{3-[3- fluoro -4-( pyridin -2- yl ) phenyl ] -1H - pyrrolo [2,3- b ] pyridine -5- yl }-6,7,8,9- tetrahydro - 5H - benzo [7] annen -7- yl ]-3- oxa -6- azabicyclo [3.1.1] heptane

The title compound was prepared in an analogous manner to Example 1 from appropriate starting materials. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.15 (d, J = 2.7 Hz, 1H), 8.77 – 8.70 (m, 1H), 8.59 – 8.53 (m, 1H), 8.49 (d, J = 2.1 Hz, 1H), 8.12 (d, J = 2.7 Hz, 1H), 8.06 (t, J = 8.4 Hz, 1H), 7.92 (td, J = 7.7, 1.8 Hz, 1H), 7.89 – 7.78 (m, 2H ), 7.80 – 7.70 (m, 1H), 7.58 – 7.52 (m, 1H), 7.53 – 7.46 (m, 1H), 7.40 (ddd, J = 7.4, 4.8, 1.2 Hz, 1H), 7.23 (d, J = 7.7 Hz, 1H), 4.16 (d, J = 10.7 Hz, 2H), 3.62 – 3.51 (m, 4H), 3.22 – 3.12 (m, 1H), 3.07 – 2.88 (m, 2H), 2.87 – 2.71 ( m, 2H), 2.41 – 2.32 (m, 1H), 1.93 – 1.79 (m, 2H), 1.68 (d, J = 7.8 Hz, 1H), 1.22 – 1.09 (m, 2H). ¹⁹ F NMR (376 MHz, DMSO- d ₆ ) δ -116.73 – -116.85 (m). ESI MS [M+H] ⁺ for C ₃₄ H ₃₂ FN ₄ O, calculated 531.3, found 531.3. Example 41 : 6-[( 7S )-2-{3-[4-( pyridin -4- yl ) phenyl ] -1H - pyrrolo [2,3- b ] pyridin -5- yl }-6 ,7,8,9- tetrahydro - 5H - benzo [7] annen -7- yl ]-3- oxa -6- azabicyclo [3.1.1] heptane

The title compound was prepared in an analogous manner to Example 1 from appropriate starting materials. ¹ H NMR (400 MHz, chloroform- d ) δ 9.27 (s, 1H), 8.73 – 8.63 (m, 2H), 8.60 (d, J = 2.1 Hz, 1H), 8.39 (d, J = 2.0 Hz, 1H ), 7.85 – 7.71 (m, 4H), 7.59 (d, J = 2.5 Hz, 1H), 7.58 – 7.52 (m, 2H), 7.41 – 7.34 (m, 2H), 7.21 (d, J = 8.3 Hz, 1H), 4.29 (d, J = 10.6 Hz, 2H), 3.71 (d, J = 10.6 Hz, 2H), 3.62 (d, J = 6.1 Hz, 2H), 3.31 – 3.20 (m, 1H), 2.98 ( td, J = 14.4, 8.0 Hz, 2H), 2.87 (d, J = 12.5 Hz, 1H), 2.80 (d, J = 13.2 Hz, 1H), 2.54 (q, J = 6.7 Hz, 1H), 2.01 – 1.88 (m, 2H), 1.83 (d, J = 8.1 Hz, 1H), 1.41 – 1.25 (m, 2H). ESI MS [M+H] ⁺ for C ₃₄ H ₃₃ N ₄ O, calculated 513.3, found 513.3. Example 42 : 6-[( 7S )-2-{3-[4-(3- fluoropyridin -2- yl ) phenyl ] -1H - pyrrolo [2,3- b ] pyridin -5- yl }-6,7,8,9- tetrahydro - 5H - benzo [7] annen -7- yl ]-3- oxa -6- azabicyclo [3.1.1] heptane

The title compound was prepared in an analogous manner to Example 1 from appropriate starting materials. ¹ H NMR (400 MHz, chloroform- d ) δ 9.32 (s, 1H), 8.62 (d, J = 2.1 Hz, 1H), 8.55 (dt, J = 4.6, 1.6 Hz, 1H), 8.44 (d, J = 1.9 Hz, 1H), 8.11 (dq, J = 8.4, 1.9 Hz, 2H), 7.85 – 7.76 (m, 2H), 7.62 (d, J = 2.6 Hz, 1H), 7.52 (ddd, J = 11.2, 8.2, 1.4 Hz, 1H), 7.44 – 7.36 (m, 2H), 7.30 – 7.26 (m, 1H), 7.22 (d, J = 8.3 Hz, 1H), 4.31 (d, J = 10.7 Hz, 2H), 3.73 (d, J = 10.7 Hz, 2H), 3.64 (d, J = 6.1 Hz, 2H), 3.32 – 3.18 (m, 1H), 3.09 – 2.92 (m, 2H), 2.88 (d, J = 12.8 Hz , 1H), 2.82 (d, J = 13.6 Hz, 1H), 2.56 (q, J = 6.7 Hz, 1H), 2.01 – 1.88 (m, 2H), 1.84 (d, J = 8.2 Hz, 1H), 1.34 (p, J = 10.5 Hz, 2H). ¹⁹ F NMR (376 MHz, chloroform- d ) δ -122.80 – -122.88 (m). ESI MS [M+H] ⁺ for C ₃₄ H ₃₂ FN ₄ O, calculated 531.3, found 531.3. Example 43 : 6-[( 7S )-2-{3-[4-(3- chloropyridin -2- yl ) phenyl ] -1H - pyrrolo [2,3- b ] pyridin -5- yl }-6,7,8,9- tetrahydro - 5H - benzo [7] annen -7- yl ]-3- oxa -6- azabicyclo [3.1.1] heptane

The title compound was prepared in an analogous manner to Example 1 from appropriate starting materials. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.07 (d, J = 2.6 Hz, 1H), 8.66 (dd, J = 4.6, 1.5 Hz, 1H), 8.56 (d, J = 2.1 Hz, 1H) , 8.48 (d, J = 2.1 Hz, 1H), 8.07 (dd, J = 8.1, 1.5 Hz, 1H), 8.03 (d, J = 2.6 Hz, 1H), 7.96 – 7.87 (m, 2H), 7.83 – 7.76 (m, 2H), 7.54 (d, J = 1.9 Hz, 1H), 7.49 (dd, J = 7.6, 1.9 Hz, 1H), 7.44 (dd, J = 8.1, 4.6 Hz, 1H), 7.23 (d , J = 7.8 Hz, 1H), 4.16 (d, J = 10.6 Hz, 2H), 3.65 – 3.46 (m, 4H), 3.22 – 3.11 (m, 1H), 3.08 – 2.87 (m, 2H), 2.78 ( q, J = 14.4, 13.9 Hz, 2H), 2.36 (q, J = 6.5, 5.8 Hz, 1H), 1.93 – 1.76 (m, 2H), 1.68 (d, J = 7.8 Hz, 1H), 1.22 – 1.08 (m, 2H). ESI MS [M+H] ⁺ for C ₃₄ H ₃₂ ClN ₄ O, calculated 547.2, found 547.2. Example 44 : 6-[( 7S )-2-{3-[3- chloro -4-( pyridin -2- yl ) phenyl ] -1H - pyrrolo [2,3- b ] pyridine -5- yl }-6,7,8,9- tetrahydro - 5H - benzo [7] annen -7- yl ]-3- oxa -6- azabicyclo [3.1.1] heptane

The title compound was prepared in an analogous manner to Example 1 from appropriate starting materials. ¹ H NMR (400 MHz, chloroform- d ) δ 9.79 (s, 1H), 8.76 (ddd, J = 4.9, 1.8, 1.0 Hz, 1H), 8.63 (s, 1H), 8.39 (d, J = 2.0 Hz , 1H), 7.82 – 7.67 (m, 5H), 7.62 (d, J = 2.5 Hz, 1H), 7.43 – 7.37 (m, 2H), 7.31 (ddd, J = 7.2, 4.9, 1.5 Hz, 1H), 7.23 (d, J = 8.2 Hz, 1H), 4.31 (d, J = 10.6 Hz, 2H), 3.73 (d, J = 10.6 Hz, 2H), 3.65 (d, J = 6.1 Hz, 2H), 3.26 ( t, J = 9.6 Hz, 1H), 3.00 (td, J = 16.5, 15.9, 7.7 Hz, 2H), 2.86 (q, J = 13.3 Hz, 2H), 2.56 (q, J = 6.8 Hz, 1H), 2.03 – 1.88 (m, 2H), 1.85 (d, J = 8.2 Hz, 1H), 1.41 – 1.30 (m, 2H). ESI MS [M+H] ⁺ for C ₃₄ H ₃₂ ClN ₄ O, calculated 547.2, found 547.2. Example 45 : 6-[( 7S )-2-{3-[1-( pyridin -4- yl ) -1H - pyrazol -4- yl ] -1H - pyrrolo [2,3- b ] Pyridin -5- yl }-6,7,8,9 - tetrahydro - 5H - benzo [7] annen -7- yl ]-3- oxa -6- azabicyclo [3.1.1] heptan alkyl

The title compound was prepared in an analogous manner to Example 1 from appropriate starting materials. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.91 (d, J = 2.6 Hz, 1H), 9.16 (s, 1H), 8.73 – 8.59 (m, 2H), 8.59 – 8.47 (m, 2H), 8.40 (s, 1H), 8.01 – 7.97 (m, 2H), 7.96 (d, J = 2.6 Hz, 1H), 7.59 – 7.53 (m, 1H), 7.51 (dd, J = 7.6, 1.7 Hz, 1H) , 7.25 (d, J = 7.7 Hz, 1H), 4.17 (d, J = 10.7 Hz, 2H), 3.64 – 3.47 (m, 4H), 3.24 – 3.12 (m, 1H), 3.08 – 2.88 (m, 2H ), 2.88 – 2.72 (m, 2H), 2.42 – 2.29 (m, 1H), 1.96 – 1.79 (m, 2H), 1.69 (d, J = 7.9 Hz, 1H), 1.25 – 1.10 (m, 2H). ESI MS [M+H] ⁺ for C ₃₁ H ₃₁ N ₆ O, calculated 503.3, found 503.2. Example 46 : 2-(4-{5-[(7 S )-7-{3- oxa -6- azabicyclo [3.1.1] hept -6- yl }-6,7,8,9- Tetrahydro -5 H -benzo [7] annen -2- yl ]-1 H -pyrrolo [2,3- b ] pyridin -3- yl } phenyl ) pyridine -3- carbonitrile

The title compound was prepared in an analogous manner to Example 1 from appropriate starting materials. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.14 (s, 1H), 8.96 (dd, J = 4.8, 1.7 Hz, 1H), 8.57 (d, J = 2.0 Hz, 1H), 8.51 (d, J = 2.0 Hz, 1H), 8.45 (dd, J = 8.0, 1.8 Hz, 1H), 8.10 (d, J = 2.7 Hz, 1H), 8.03 (d, J = 8.5 Hz, 2H), 7.99 (d, J = 8.5 Hz, 2H), 7.61 (dd, J = 7.9, 4.8 Hz, 1H), 7.56 (d, J = 2.0 Hz, 1H), 7.50 (dd, J = 7.7, 1.7 Hz, 1H), 7.23 ( d, J = 7.7 Hz, 1H), 4.16 (d, J = 10.6 Hz, 2H), 3.65 – 3.48 (m, 4H), 3.22 – 3.09 (m, 1H), 3.07 – 2.87 (m, 2H), 2.87 – 2.70 (m, 2H), 2.41 – 2.28 (m, 1H), 1.96 – 1.78 (m, 2H), 1.68 (d, J = 7.9 Hz, 1H), 1.24 – 1.08 (m, 2H). ESI MS [M+H] ⁺ for C ₃₅ H ₃₂ N ₅ O, calculated 538.3, found 538.2. Example 47 : 6-[( 7S )-2-{3-[4-(5- methylpyrimidin -4- yl ) phenyl ] -1H - pyrrolo [2,3- b ] pyridine -5- yl }-6,7,8,9- tetrahydro - 5H - benzo [7] annen -7- yl ]-3- oxa -6- azabicyclo [3.1.1] heptane

The title compound was prepared in an analogous manner to Example 1 from appropriate starting materials. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.11 (d, J = 2.7 Hz, 1H), 9.10 (s, 1H), 8.74 (s, 1H), 8.57 (d, J = 2.1 Hz, 1H) , 8.49 (d, J = 2.1 Hz, 1H), 8.07 (d, J = 2.7 Hz, 1H), 7.97 (dt, J = 8.5, 1.9 Hz, 2H), 7.82 (dt, J = 8.5, 2.0 Hz, 2H), 7.55 (d, J = 2.0 Hz, 1H), 7.49 (dd, J = 7.6, 2.0 Hz, 1H), 7.23 (d, J = 7.8 Hz, 1H), 4.16 (d, J = 10.6 Hz, 2H), 3.59 (d, J = 10.6 Hz, 2H), 3.54 (d, J = 6.0 Hz, 2H), 3.23 – 3.09 (m, 1H), 3.09 – 2.86 (m, 2H), 2.79 (q, J = 14.3 Hz, 2H), 2.45 (s, 3H), 2.41 – 2.26 (m, 1H), 1.95 – 1.75 (m, 2H), 1.68 (d, J = 7.8 Hz, 1H), 1.28 – 1.05 (m, 2H). ESI MS [M+H] ⁺ for C ₃₄ H ₃₄ N ₅ O, calculated 528.3, found 528.3. Example 48 : 6-[( 7S )-2-{3-[4-(3- methylpyrazin -2- yl ) phenyl ] -1H - pyrrolo [2,3- b ] pyridine -5 -yl } -6,7,8,9 - tetrahydro - 5H - benzo [7] annen -7- yl ]-3- oxa -6- azabicyclo [3.1.1] heptane

The title compound was prepared in an analogous manner to Example 1 from appropriate starting materials. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.09 (d, J = 2.7 Hz, 1H), 8.59 – 8.57 (m, 1H), 8.56 (d, J = 2.1 Hz, 1H), 8.52 (d, J = 2.5 Hz, 1H), 8.48 (d, J = 2.1 Hz, 1H), 8.04 (d, J = 2.7 Hz, 1H), 7.99 – 7.91 (m, 2H), 7.78 – 7.70 (m, 2H), 7.54 (d, J = 1.9 Hz, 1H), 7.48 (dd, J = 7.9, 1.8 Hz, 1H), 7.23 (d, J = 7.8 Hz, 1H), 4.15 (d, J = 10.5 Hz, 2H), 3.58 (d, J = 10.6 Hz, 2H), 3.54 (d, J = 6.0 Hz, 2H), 3.22 – 3.09 (m, 1H), 3.09 – 2.85 (m, 2H), 2.78 (q, J = 13.8 Hz , 2H), 2.66 (s, 3H), 2.36 (q, J = 7.2, 6.7 Hz, 1H), 1.94 – 1.73 (m, 2H), 1.68 (d, J = 7.8 Hz, 1H), 1.29 – 1.02 ( m, 2H). ESI MS [M+H] ⁺ for C ₃₄ H ₃₄ N ₅ O, calculated 528.3, found 528.3. Example 49 : 6-[( 7S )-2-{3-[4-(4- methylpyridazin -3- yl ) phenyl ] -1H - pyrrolo [2,3- b ] pyridine -5 -yl } -6,7,8,9 - tetrahydro - 5H - benzo [7] annen -7- yl ]-3- oxa -6- azabicyclo [3.1.1] heptane

The title compound was prepared in an analogous manner to Example 1 from appropriate starting materials. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.09 (d, J = 2.8 Hz, 1H), 9.08 (d, J = 5.2 Hz, 1H), 8.57 (d, J = 2.0 Hz, 1H), 8.49 (d, J = 2.1 Hz, 1H), 8.05 (d, J = 2.6 Hz, 1H), 8.00 – 7.90 (m, 2H), 7.80 – 7.68 (m, 2H), 7.66 (dd, J = 5.2, 1.0 Hz, 1H), 7.55 (d, J = 1.8 Hz, 1H), 7.49 (dd, J = 7.5, 2.0 Hz, 1H), 7.23 (d, J = 7.8 Hz, 1H), 4.16 (d, J = 10.6 Hz, 2H), 3.68 – 3.46 (m, 4H), 3.24 – 3.07 (m, 1H), 3.06 – 2.87 (m, 2H), 2.79 (q, J = 14.4, 13.9 Hz, 2H), 2.42 (s, 3H), 2.41 – 2.28 (m, 1H), 1.93 – 1.80 (m, 2H), 1.68 (d, J = 7.9 Hz, 1H), 1.26 – 1.00 (m, 2H). ESI MS [M+H] ⁺ for C ₃₄ H ₃₄ N ₅ O, calculated 528.3, found 528.3. Example 50 : 6-[( 7S )-2-{3-[4-(3,5- dimethylpyrazin- 2- yl ) phenyl ] -1H - pyrrolo [2,3- b ] Pyridin -5- yl }-6,7,8,9 - tetrahydro - 5H - benzo [7] annen -7- yl ]-3- oxa -6- azabicyclo [3.1.1] heptan alkyl

The title compound was prepared in an analogous manner to Example 1 from appropriate starting materials. ¹ H NMR (400 MHz, chloroform- d ) δ 10.21 (s, 1H), 8.64 (d, J = 2.0 Hz, 1H), 8.44 (d, J = 2.0 Hz, 1H), 8.40 (s, 1H), 7.87 – 7.75 (m, 2H), 7.75 – 7.66 (m, 2H), 7.63 (d, J = 2.5 Hz, 1H), 7.47 – 7.35 (m, 2H), 7.23 (d, J = 8.3 Hz, 1H) , 4.31 (d, J = 10.6 Hz, 2H), 3.73 (d, J = 10.7 Hz, 2H), 3.65 (d, J = 6.1 Hz, 2H), 3.32 – 3.17 (m, 1H), 3.00 (td, J = 17.1, 16.1, 7.9 Hz, 2H), 2.86 (q, J = 13.6 Hz, 2H), 2.70 (s, 3H), 2.60 (s, 3H), 2.56 (q, J = 6.4 Hz, 1H), 2.04 – 1.89 (m, 2H), 1.85 (d, J = 8.2 Hz, 1H), 1.34 (p, J = 10.1 Hz, 2H). ESI MS [M+H] ⁺ for C ₃₅ H ₃₆ N ₅ O, calculated 542.3, found 542.3. Example 51 : 4- methyl -3-(4-{5-[(7 S )-7- methyl- 7-[(2 R )-2- methylpyrrolidin -1- yl ]-6,7 ,8,9- tetrahydro -5 H -benzo [7] annen -2- yl ]-1 H -pyrrolo [2,3- b ] pyridin -3- yl } phenyl ) pyridazine

The title compound was prepared in an analogous manner to Example 1 from appropriate starting materials. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.08 (s, 1H), 9.08 (d, J = 5.1 Hz, 1H), 8.56 (d, J = 2.1 Hz, 1H), 8.48 (d, J = 2.0 Hz, 1H), 8.05 (d, J = 2.7 Hz, 1H), 8.00 – 7.84 (m, 2H), 7.78 – 7.68 (m, 2H), 7.66 (dt, J = 5.1, 0.7 Hz, 1H), 7.51 (s, 1H), 7.46 (d, J = 7.8 Hz, 1H), 7.20 (d, J = 7.7 Hz, 1H), 3.29 – 3.09 (m, 3H), 2.83 (t, J = 7.6 Hz, 1H ), 2.71 – 2.52 (m, 3H), 2.42 (s, 3H), 1.96 – 1.57 (m, 5H), 1.46 – 1.20 (m, 3H), 1.03 (d, J = 6.2 Hz, 3H), 0.92 ( s, 3H). ESI MS [M+H] ⁺ for C ₃₅ H ₃₈ N ₅ , calculated 528.3, found 528.3. Example 52 : 2-(4-{5-[(7 S )-7-{3- oxa -6- azabicyclo [3.1.1] hept -6- yl }-6,7,8,9- Tetrahydro -5 H -benzo [7] annen -2- yl ]-1 H -pyrazolo [3,4- b ] pyridin -3- yl } phenyl ) pyridine -3- carbonitrile

The title compound was prepared in an analogous manner to Example 2 from appropriate starting materials. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.03 – 8.93 (m, 1H), 8.89 (d, J = 2.0 Hz, 1H), 8.78 (d, J = 2.1 Hz, 1H), 8.48 (dd, J = 7.9, 1.7 Hz, 1H), 8.42 – 8.26 (m, 2H), 8.18 – 7.96 (m, 2H), 7.70 – 7.59 (m, 2H), 7.58 (d, J = 7.7 Hz, 1H), 7.26 (d, J = 7.7 Hz, 1H), 4.16 (d, J = 11.0 Hz, 2H), 3.71 – 3.44 (m, 4H), 3.23 – 3.10 (m, 1H), 3.10 – 2.89 (m, 2H), 2.89 – 2.71 (m, 2H), 2.42 – 2.28 (m, 1H), 2.00 – 1.79 (m, 2H), 1.68 (d, J = 7.7 Hz, 1H), 1.24 – 1.09 (m, 2H). ESI MS [M+H] ⁺ for C ₃₄ H ₃₁ N ₆ O, calculated 539.3, found 539.3. Example 53 : 6-[( 7S )-2-{3-[4-(3,6- dimethylpyrazin- 2- yl ) phenyl ] -1H - pyrrolo [2,3- b ] Pyridin -5- yl }-6,7,8,9 - tetrahydro - 5H - benzo [7] annen -7- yl ]-3- oxa -6- azabicyclo [3.1.1] heptan alkyl

The title compound was prepared in an analogous manner to Example 1 from appropriate starting materials. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.08 (d, J = 2.7 Hz, 1H), 8.56 (d, J = 2.1 Hz, 1H), 8.48 (d, J = 2.0 Hz, 1H), 8.41 (s, 1H), 8.03 (d, J = 2.7 Hz, 1H), 7.97 – 7.88 (m, 2H), 7.77 – 7.65 (m, 2H), 7.54 (d, J = 1.9 Hz, 1H), 7.48 ( dd, J = 7.7, 2.0 Hz, 1H), 7.23 (d, J = 7.8 Hz, 1H), 4.15 (d, J = 10.6 Hz, 2H), 3.58 (d, J = 10.6 Hz, 2H), 3.54 ( d, J = 6.0 Hz, 2H), 3.17 (t, J = 8.5 Hz, 1H), 2.97 (ddd, J = 33.5, 13.7, 8.6 Hz, 2H), 2.78 (q, J = 13.8 Hz, 2H), 2.60 (s, 3H), 2.52 (s, 3H), 2.36 (q, J = 6.9 Hz, 1H), 1.94 – 1.76 (m, 2H), 1.68 (d, J = 7.9 Hz, 1H), 1.26 – 1.07 (m, 2H). ESI MS [M+H] ⁺ for C ₃₅ H ₃₆ N ₅ O, calculated 542.3, found 542.3. Example 54 : 6-[(7 S )-2-{3-[5-(3- methylpyrazin -2- yl ) pyridin -2- yl ]-1 H -pyrrolo [2,3- b ] Pyridin -5- yl }-6,7,8,9 - tetrahydro - 5H - benzo [7] annen -7- yl ]-3- oxa -6- azabicyclo [3.1.1] heptan alkyl

The title compound was prepared in an analogous manner to Example 9 from appropriate starting materials. ¹ H NMR (400 MHz, chloroform- d ) δ 10.75 (d, J = 13.3 Hz, 1H), 8.97 (d, J = 1.7 Hz, 1H), 8.95 (dt, J = 2.3, 0.7 Hz, 1H), 8.64 (s, 1H), 8.55 (dt, J = 2.5, 0.7 Hz, 1H), 8.50 (d, J = 2.4 Hz, 1H), 8.05 (s, 1H), 8.01 (dd, J = 8.2, 2.5 Hz , 1H), 7.83 (dt, J = 8.3, 0.7 Hz, 1H), 7.49 – 7.41 (m, 2H), 7.24 (d, J = 8.2 Hz, 1H), 4.32 (d, J = 10.7 Hz, 2H) , 3.75 (d, J = 10.7 Hz, 2H), 3.68 (d, J = 6.1 Hz, 2H), 3.27 (t, J = 9.7 Hz, 1H), 3.00 (ddd, J = 20.7, 14.4, 7.8 Hz, 2H), 2.95 – 2.79 (m, 2H), 2.76 (s, 3H), 2.58 (q, J = 6.6 Hz, 1H), 2.03 – 1.91 (m, 2H), 1.86 (d, J = 8.3 Hz, 1H ), 1.36 (p, J = 9.8 Hz, 2H). ESI MS [M+H] ⁺ for C ₃₃ H ₃₃ N ₆ O, calculated 529.3, found 529.3. Example 55 : 6-[( 7S )-2-{3-[5-(3- methylpyrazin -2- yl ) pyridin -2- yl ] -1H - pyrazolo [3,4- b ] pyridin -5- yl }-6,7,8,9 - tetrahydro - 5H - benzo [7] annen -7- yl ]-3- oxa -6- azabicyclo [3.1.1] Heptane

The title compound was prepared in an analogous manner to Example 9 from appropriate starting materials. ¹ H NMR (400 MHz, chloroform- d ) δ 12.16 (s, 1H), 9.19 (s, 1H), 9.11 – 8.96 (m, 1H), 8.88 (s, 1H), 8.58 – 8.55 (m, 1H) , 8.53 (d, J = 2.4 Hz, 1H), 8.38 (dt, J = 8.2, 0.9 Hz, 1H), 8.09 (ddd, J = 8.3, 2.3, 0.8 Hz, 1H), 7.51 – 7.36 (m, 2H ), 7.26 – 7.22 (m, 1H), 4.33 (d, J = 10.7 Hz, 2H), 3.75 (d, J = 10.7 Hz, 2H), 3.68 (d, J = 6.1 Hz, 2H), 3.35 – 3.20 (m, 1H), 3.08 – 2.78 (m, 4H), 2.76 (s, 3H), 2.60 (q, J = 6.9 Hz, 1H), 2.08 – 1.89 (m, 2H), 1.87 (d, J = 8.2 Hz, 1H), 1.46 – 1.28 (m, 2H). ESI MS [M+H] ⁺ for C ₃₂ H ₃₂ N ₇ O, calculated 530.3, found 530.3. Example 56 : 6-[( 7S )-2-{3-[5-(4- methylpyridazin -3- yl ) pyridin -2- yl ] -1H - pyrazolo [3,4- b ] pyridin -5- yl }-6,7,8,9 - tetrahydro - 5H - benzo [7] annen -7- yl ]-3- oxa -6- azabicyclo [3.1.1] Heptane

The title compound was prepared in an analogous manner to Example 9 from appropriate starting materials. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.15 (d, J = 5.2 Hz, 1H), 9.07 (d, J = 2.2 Hz, 1H), 9.06 – 9.03 (m, 1H), 8.90 (d, J = 2.2 Hz, 1H), 8.36 (dd, J = 8.2, 0.8 Hz, 1H), 8.25 (dd, J = 8.3, 2.2 Hz, 1H), 7.73 (dt, J = 5.1, 0.7 Hz, 1H), 7.54 (s, 1H), 7.48 (dd, J = 7.7, 1.9 Hz, 1H), 7.28 (d, J = 7.7 Hz, 1H), 4.16 (d, J = 10.6 Hz, 2H), 3.66 – 3.44 (m , 4H), 3.25 – 3.09 (m, 1H), 3.09 – 2.88 (m, 2H), 2.80 (q, J = 13.9 Hz, 2H), 2.46 (s, 3H), 2.36 (q, J = 7.2 Hz, 1H), 2.03 – 1.78 (m, 2H), 1.68 (d, J = 7.9 Hz, 1H), 1.29 – 0.97 (m, 2H). ESI MS [M+H] ⁺ for C ₃₂ H ₃₂ N ₇ O, calculated 530.3, found 530.3. Example 57 : 3,5- dimethyl -2-(4-{5-[(7 S )-7- methyl -7-[(2 R )-2- methylpyrrolidin -1- yl ]- 6,7,8,9- tetrahydro -5 H -benzo [7] annen -2- yl ]-1 H -pyrrolo [2,3- b ] pyridin -3- yl } phenyl ) pyrazine

The title compound was prepared in an analogous manner to Example 1 from appropriate starting materials. ¹ H NMR (400 MHz, chloroform- d ) δ 9.27 (s, 1H), 8.62 (d, J = 2.0 Hz, 1H), 8.42 (d, J = 1.8 Hz, 1H), 8.40 (s, 1H), 7.87 – 7.73 (m, 2H), 7.73 – 7.64 (m, 2H), 7.60 (d, J = 2.5 Hz, 1H), 7.42 – 7.34 (m, 2H), 7.21 (d, J = 8.1 Hz, 1H) , 3.52 – 3.29 (m, 1H), 3.24 (p, J = 6.5 Hz, 2H), 2.92 (t, J = 7.6 Hz, 1H), 2.77 – 2.44 (m, 9H), 2.01 – 1.78 (m, 3H ), 1.79 – 1.62 (m, 2H), 1.55 – 1.37 (m, 3H), 1.08 (d, J = 6.3 Hz, 3H), 1.00 (s, 3H). ESI MS [M+H] ⁺ for C ₃₆ H ₄₀ N ₅ , calculated 542.3, found 542.3. Example 58 : 2,5- dimethyl -3-(4-{5-[(7 S )-7- methyl -7-[(2 R )-2- methylpyrrolidin -1- yl ]- 6,7,8,9- tetrahydro -5 H -benzo [7] annen -2- yl ]-1 H -pyrrolo [2,3- b ] pyridin -3- yl } phenyl ) pyrazine

The title compound was prepared in an analogous manner to Example 1 from appropriate starting materials. ¹ H NMR (400 MHz, chloroform- d ) δ 9.32 (s, 1H), 8.62 (d, J = 2.0 Hz, 1H), 8.42 (d, J = 2.0 Hz, 1H), 8.35 (s, 1H), 7.89 – 7.74 (m, 2H), 7.74 – 7.65 (m, 2H), 7.60 (d, J = 2.5 Hz, 1H), 7.42 – 7.33 (m, 2H), 7.21 (d, J = 8.2 Hz, 1H) , 3.52 – 3.30 (m, 1H), 3.30 – 3.17 (m, 2H), 2.92 (t, J = 7.6 Hz, 1H), 2.74 – 2.63 (m, 4H), 2.64 – 2.45 (m, 5H), 1.99 – 1.80 (m, 3H), 1.79 – 1.62 (m, 2H), 1.56 – 1.39 (m, 3H), 1.08 (d, J = 6.3 Hz, 3H), 1.00 (s, 3H). ESI MS [M+H] ⁺ for C ₃₆ H ₄₀ N ₅ , calculated 542.3, found 542.3. Example 59 : 3,5- dimethyl -2-(4-{5-[(7 S )-7-( pyrrolidin -1- yl )-6,7,8,9- tetrahydro - 5H - Benzo [7] annen -2- yl ]-1 H -pyrrolo [2,3- b ] pyridin -3- yl } phenyl ) pyrazine

The title compound was prepared in an analogous manner to Example 1 from appropriate starting materials. ¹ H NMR (400 MHz, chloroform- d ) δ 9.20 (s, 1H), 8.62 (s, 1H), 8.43 (d, J = 1.3 Hz, 1H), 8.40 (s, 1H), 7.83 – 7.75 (m , 2H), 7.70 (dt, J = 8.3, 0.7 Hz, 2H), 7.60 (d, J = 2.3 Hz, 1H), 7.42 – 7.37 (m, 2H), 7.23 (d, J = 7.8 Hz, 1H) , 3.15 – 2.95 (m, 2H), 2.82 – 2.68 (m, 5H), 2.69 – 2.50 (m, 8H), 2.19 – 2.01 (m, 2H), 1.87 – 1.73 (m, 4H), 1.68 – 1.60 ( m, 2H). ESI MS [M+H] ⁺ for C ₃₄ H ₃₆ N ₅ , calculated 514.3, found 514.3. Example 60 : 3,5- dimethyl -2-(6-{5-[(7 S )-7- methyl -7-[(2 R )-2- methylpyrrolidin -1- yl ]- 6,7,8,9- tetrahydro -5 H -benzo [7] annen -2- yl ]-1 H -pyrazolo [3,4- b ] pyridin - 3- yl } pyridin -3- pyrazine _ _

The title compound was prepared in an analogous manner to Example 9 from appropriate starting materials. ¹ H NMR (400 MHz, chloroform- d ) δ 11.62 (s, 1H), 9.20 (d, J = 1.9 Hz, 1H), 8.99 (dd, J = 2.3, 0.9 Hz, 1H), 8.90 (s, 1H ), 8.44 (s, 1H), 8.36 (dd, J = 8.2, 0.9 Hz, 1H), 8.07 (dd, J = 8.2, 2.3 Hz, 1H), 7.49 – 7.37 (m, 2H), 7.23 (d, J = 8.1 Hz, 1H), 3.48 – 3.33 (m, 1H), 3.33 – 3.17 (m, 2H), 2.93 (t, J = 7.7 Hz, 1H), 2.77 – 2.57 (m, 8H), 2.58 – 2.45 (m, 1H), 2.02 – 1.79 (m, 3H), 1.80 – 1.64 (m, 2H), 1.56 – 1.39 (m, 3H), 1.09 (d, J = 6.5 Hz, 3H), 1.00 (s, 3H ). ESI MS [M+H] ⁺ for C ₃₄ H ₃₈ N ₇ , calculated 544.3, found 544.3. Example 61 : 2,5- dimethyl -3-(6-{5-[(7 S )-7- methyl -7-[(2 R )-2- methylpyrrolidin -1- yl ]- 6,7,8,9- tetrahydro -5 H -benzo [7] annen -2- yl ]-1 H -pyrazolo [3,4- b ] pyridin - 3- yl } pyridin -3- pyrazine _ _

The title compound was prepared in an analogous manner to Example 9 from appropriate starting materials. ¹ H NMR (400 MHz, chloroform- d ) δ 11.68 (s, 1H), 9.20 (s, 1H), 9.00 (dt, J = 2.3, 0.7 Hz, 1H), 8.91 (s, 1H), 8.41 (s , 1H), 8.36 (dt, J = 8.3, 0.7 Hz, 1H), 8.08 (dd, J = 8.1, 2.1 Hz, 1H), 7.48 – 7.39 (m, 2H), 7.24 (d, J = 8.2 Hz, 1H), 3.53 – 3.34 (m, 1H), 3.34 – 3.16 (m, 2H), 2.93 (t, J = 7.6 Hz, 1H), 2.76 – 2.58 (m, 8H), 2.59 – 2.44 (m, 1H) , 2.03 – 1.80 (m, 3H), 1.80 – 1.63 (m, 2H), 1.58 – 1.37 (m, 3H), 1.09 (d, J = 6.3 Hz, 3H), 1.01 (s, 3H). ESI MS [M+H] ⁺ for C ₃₄ H ₃₈ N ₇ , calculated 544.3, found 544.3. Example 62 : (1 S ,4 S )-5-[(7 S )-2-{3-[4-(3,6- dimethylpyrazin -2- yl ) phenyl ]-1 H -pyrrole And [2,3- b ] pyridin -5- yl }-6,7,8,9 - tetrahydro -5 H -benzo [7] annen -7- yl ]-2- oxa -5- nitrogen Heterobicyclo [2.2.1] heptane

The title compound was prepared in an analogous manner to Example 1 from appropriate starting materials. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.07 (s, 1H), 8.56 (d, J = 2.1 Hz, 1H), 8.47 (d, J = 2.1 Hz, 1H), 8.41 (s, 1H) , 8.02 (d, J = 2.6 Hz, 1H), 7.97 – 7.86 (m, 2H), 7.79 – 7.61 (m, 2H), 7.54 (s, 1H), 7.48 (d, J = 8.0 Hz, 1H), 7.22 (d, J = 7.7 Hz, 1H), 4.34 (s, 1H), 3.91 (d, J = 7.5 Hz, 1H), 3.71 (s, 1H), 3.54 (d, J = 7.4 Hz, 1H), 3.18 – 2.93 (m, 3H), 2.80 – 2.61 (m, 3H), 2.60 (s, 3H), 2.52 (s, 3H), 2.35 (d, J = 9.8 Hz, 1H), 2.00 – 1.76 (m, 2H), 1.73 (d, J = 9.3 Hz, 1H), 1.62 (d, J = 9.3 Hz, 1H), 1.58 – 1.30 (m, 2H). ESI MS [M+H] ⁺ for C ₃₅ H ₃₆ N ₅ O, calculated 542.3, found 542.3. Example 63 : 3-(4-{5-[(7 S )-7-[(3 S )-3-( methoxymethyl ) pyrrolidin -1- yl ]-6,7,8,9- Tetrahydro -5 H -benzo [7] annen -2- yl ]-1 H -pyrrolo [2,3- b ] pyridin -3- yl } phenyl )-2,5- dimethylpyrazine

The title compound was prepared in an analogous manner to Example 1 from appropriate starting materials. ¹ H NMR (400 MHz, chloroform- d ) δ 9.29 (s, 1H), 8.62 (d, J = 2.0 Hz, 1H), 8.42 (d, J = 2.1 Hz, 1H), 8.35 (s, 1H), 7.83 – 7.74 (m, 2H), 7.73 – 7.65 (m, 2H), 7.60 (d, J = 2.5 Hz, 1H), 7.43 – 7.34 (m, 2H), 7.22 (d, J = 7.7 Hz, 1H) , 3.35 (s, 3H), 3.32 (dd, J = 7.0, 4.0 Hz, 2H), 3.21 – 3.00 (m, 2H), 2.88 – 2.77 (m, 1H), 2.77 – 2.62 (m, 7H), 2.61 (s, 3H), 2.57 – 2.49 (m, 1H), 2.49 – 2.36 (m, 2H), 2.13 – 1.83 (m, 3H), 1.75 – 1.61 (m, 2H), 1.54 – 1.36 (m, 1H) . ESI MS [M+H] ⁺ for C ₃₆ H ₄₀ N ₅ O, calculated 558.3, found 558.3. Example 64 : 2,5- dimethyl -3-(4-{5-[(7 S )-7- methyl -7-[(2 R )-2- methylpyrrolidin -1- yl ]- 6,7,8,9- tetrahydro -5 H -benzo [7] annen -2- yl ]-1 H -pyrazolo [3,4- b ] pyridin - 3- yl } phenyl ) pyra Azine

The title compound was prepared in an analogous manner to Example 2 from appropriate starting materials. ¹ H NMR (400 MHz, chloroform- d ) δ 11.62 (s, 1H), 8.90 (d, J = 2.0 Hz, 1H), 8.53 (d, J = 2.0 Hz, 1H), 8.38 (s, 1H), 8.20 – 8.03 (m, 2H), 7.82 – 7.70 (m, 2H), 7.46 – 7.33 (m, 2H), 7.24 (d, J = 8.2 Hz, 1H), 3.55 – 3.33 (m, 1H), 3.33 – 3.16 (m, 2H), 2.93 (t, J = 7.4 Hz, 1H), 2.74 – 2.48 (m, 9H), 2.02 – 1.80 (m, 3H), 1.80 – 1.63 (m, 2H), 1.58 – 1.39 ( m, 3H), 1.09 (d, J = 6.3 Hz, 3H), 1.00 (s, 3H). ESI MS [M+H] ⁺ for C ₃₅ H ₃₉ N ₆ , calculated 543.3, found 543.3. Example 65 : 6-[( 7S )-2-{3-[4-(3,6- dimethylpyrazin- 2- yl ) phenyl ] -1H - pyrazolo [3,4- b ] pyridin -5- yl }-6,7,8,9 - tetrahydro - 5H - benzo [7] annen -7- yl ]-3- oxa -6- azabicyclo [3.1.1] Heptane

The title compound was prepared in an analogous manner to Example 2 from appropriate starting materials. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 13.97 (s, 1H), 8.88 (d, J = 2.0 Hz, 1H), 8.74 (d, J = 2.0 Hz, 1H), 8.44 (s, 1H) , 8.25 (d, J = 8.3 Hz, 2H), 7.81 (d, J = 8.2 Hz, 2H), 7.63 (s, 1H), 7.56 (d, J = 7.9 Hz, 1H), 7.26 (d, J = 7.8 Hz, 1H), 4.16 (d, J = 10.6 Hz, 2H), 3.66 – 3.42 (m, 4H), 3.24 – 3.11 (m, 1H), 3.11 – 2.87 (m, 2H), 2.88 – 2.71 (m , 2H), 2.61 (s, 3H), 2.53 (s, 3H), 2.41 – 2.30 (m, 1H), 2.01 – 1.76 (m, 2H), 1.69 (d, J = 8.1 Hz, 1H), 1.26 – 0.98 (m, 2H). ESI MS [M+H] ⁺ for C ₃₄ H ₃₅ N ₆ O, calculated 543.3, found 543.3. Example 66 : 2-(4-{5-[(7 S )-7- methyl- 7-[(2 R )-2- methylpyrrolidin -1- yl ]-6,7,8,9- Tetrahydro -5 H -benzo [7] annen -2- yl ]-1 H -pyrazolo [3,4- b ] pyridin -3- yl } phenyl ) pyridine -3- carbonitrile

The title compound was prepared in an analogous manner to Example 2 from appropriate starting materials. ¹ H NMR (400 MHz, chloroform- d ) δ 11.68 (s, 1H), 8.93 (dd, J = 4.8, 1.8 Hz, 1H), 8.91 (d, J = 2.0 Hz, 1H), 8.56 (d, J = 2.0 Hz, 1H), 8.26 – 8.19 (m, 2H), 8.18 – 8.11 (m, 3H), 7.48 – 7.36 (m, 3H), 7.24 (d, J = 7.9 Hz, 1H), 3.49 – 3.34 ( m, 1H), 3.34 – 3.12 (m, 2H), 2.93 (t, J = 7.7 Hz, 1H), 2.77 – 2.43 (m, 3H), 2.02 – 1.80 (m, 3H), 1.79 – 1.66 (m, 2H), 1.58 – 1.41 (m, 3H), 1.09 (d, J = 6.3 Hz, 3H), 1.01 (s, 3H). ESI MS [M+H] ⁺ for C ₃₅ H ₃₅ N ₆ , calculated 539.3, found 539.3. Example 67 : 3- Methyl -2-(4-{5-[7-( pyrrolidin -1- yl )-5,6,7,8- tetralin -2- yl ]-1 H -pyrazole And [3,4- b ] pyridin -3- yl } phenyl ) pyridine

The title compound was prepared in an analogous manner to Example 19 from appropriate starting materials. ¹ H NMR (400 MHz, chloroform- d ) δ 11.28 (s, 1H), 8.86 (dd, J = 2.1, 1.0 Hz, 1H), 8.58 (d, J = 4.8 Hz, 1H), 8.54 – 8.43 (m , 1H), 8.19 – 8.01 (m, 2H), 7.73 (d, J = 8.1 Hz, 2H), 7.63 (d, J = 7.7 Hz, 1H), 7.45 – 7.32 (m, 2H), 7.25 – 7.20 ( m, 2H), 3.19 (dd, J = 16.4, 4.4 Hz, 1H), 3.05 – 2.82 (m, 3H), 2.83 – 2.63 (m, 4H), 2.60 – 2.47 (m, 1H), 2.45 (s, 3H), 2.35 – 2.19 (m, 1H), 1.99 – 1.81 (m, 4H), 1.83 – 1.69 (m, 1H). ESI MS [M+H] ⁺ for C ₃₂ H ₃₂ N ₅ , calculated 486.3, found 486.3. Example 68 : 2,5- dimethyl -3-(6-{5-[(7 S )-7- methyl -7-[(2 R )-2- methylpyrrolidin -1- yl ]- 6,7,8,9- tetrahydro -5 H -benzo [7] annuen -2- yl ]-1 H -pyrrolo [2,3- b ] pyridin - 3- yl } pyridin -3- yl ) pyrazine

The title compound was prepared in an analogous manner to Example 9 from appropriate starting materials. ¹ H NMR (400 MHz, chloroform- d ) δ 10.09 (s, 1H), 8.94 (d, J = 2.1 Hz, 1H), 8.92 (dd, J = 2.4, 0.8 Hz, 1H), 8.64 (d, J = 2.1 Hz, 1H), 8.38 (s, 1H), 8.02 (d, J = 2.6 Hz, 1H), 7.99 (dd, J = 8.2, 2.3 Hz, 1H), 7.82 (dd, J = 8.2, 0.9 Hz , 1H), 7.47 – 7.37 (m, 2H), 7.22 (d, J = 8.2 Hz, 1H), 3.52 – 3.34 (m, 1H), 3.25 (p, J = 7.0, 6.5 Hz, 2H), 2.98 – 2.88 (m, 1H), 2.74 – 2.57 (m, 8H), 2.57 – 2.48 (m, 1H), 2.02 – 1.80 (m, 3H), 1.80 – 1.64 (m, 2H), 1.59 – 1.39 (m, 3H ), 1.08 (d, J = 6.3 Hz, 3H), 1.01 (s, 3H). ESI MS [M+H] ⁺ for C ₃₅ H ₃₉ N ₆ , calculated 543.3, found 543.3. Example 69 : 6-[(7 S )-2-{3-[5-(3,6- dimethylpyrazin -2- yl ) pyridin -2- yl ]-1 H -pyrrolo [2,3 - b ] pyridin -5- yl }-6,7,8,9 - tetrahydro -5 H -benzo [7] annen -7- yl ]-3- oxa -6- azabicyclo [3.1. 1] Heptane

The title compound was prepared in an analogous manner to Example 9 from appropriate starting materials. ¹ H NMR (400 MHz, chloroform- d ) δ 10.38 (s, 1H), 9.03 – 8.79 (m, 2H), 8.63 (s, 1H), 8.42 – 8.26 (m, 1H), 8.11 – 7.90 (m, 2H), 7.81 (dd, J = 8.2, 4.0 Hz, 1H), 7.48 – 7.30 (m, 2H), 7.25 – 7.20 (m, 1H), 4.32 (d, J = 9.8 Hz, 2H), 3.73 (dd , J = 11.3, 3.7 Hz, 2H), 3.66 (d, J = 5.9 Hz, 2H), 3.33 – 3.17 (m, 1H), 3.09 – 2.76 (m, 4H), 2.70 (s, 3H), 2.62 ( s, 3H), 2.58 – 2.50 (m, 1H), 2.06 – 1.88 (m, 2H), 1.85 (d, J = 8.3 Hz, 1H), 1.41 – 1.24 (m, 2H). ESI MS [M+H] ⁺ for C ₃₄ H ₃₅ N ₆ O, calculated 543.3, found 543.3. Example 70 : 6- methyl -2-(4-{5-[(7 S )-7-{3- oxa -6- azabicyclo [3.1.1] hept -6- yl }-6,7 ,8,9- tetrahydro -5 H -benzo [7] annen -2- yl ]-1 H -pyrazolo [3,4- b ] pyridin - 3- yl } phenyl ) pyridine -3- Carbonitrile

The title compound was prepared in an analogous manner to Example 2 from appropriate starting materials. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.89 (d, J = 2.0 Hz, 1H), 8.77 (d, J = 2.0 Hz, 1H), 8.42 – 8.24 (m, 3H), 8.05 (d, J = 8.4 Hz, 2H), 7.64 (s, 1H), 7.58 (d, J = 7.7 Hz, 1H), 7.51 (d, J = 8.1 Hz, 1H), 7.26 (d, J = 7.7 Hz, 1H) , 4.16 (d, J = 10.7 Hz, 2H), 3.70 – 3.43 (m, 4H), 3.25 – 3.08 (m, 1H), 3.08 – 2.88 (m, 2H), 2.88 – 2.68 (m, 2H), 2.66 (s, 3H), 2.43 – 2.27 (m, 1H), 2.00 – 1.76 (m, 2H), 1.69 (d, J = 7.9 Hz, 1H), 1.25 – 1.08 (m, 2H). ESI MS [M+H] ⁺ for C ₃₅ H ₃₃ N ₆ O, calculated 553.3, found 553.3. Example 71 : 6- methyl -2-(4-{5-[(7 S )-7- methyl- 7-[(2 R )-2- methylpyrrolidin -1- yl ]-6,7 ,8,9- tetrahydro -5 H -benzo [7] annen -2- yl ]-1 H -pyrazolo [3,4- b ] pyridin - 3- yl } phenyl ) pyridine -3- Carbonitrile

The title compound was prepared in an analogous manner to Example 2 from appropriate starting materials. ¹ H NMR (400 MHz, chloroform- d ) δ 11.44 (s, 1H), 8.89 (d, J = 2.0 Hz, 1H), 8.55 (d, J = 2.0 Hz, 1H), 8.26 – 8.17 (m, 2H ), 8.17 – 8.09 (m, 2H), 7.99 (d, J = 8.0 Hz, 1H), 7.43 – 7.34 (m, 2H), 7.29 – 7.26 (m, 1H), 7.24 (d, J = 8.2 Hz, 1H), 3.56 – 3.35 (m, 1H), 3.32 – 3.16 (m, 2H), 2.93 (t, J = 7.6 Hz, 1H), 2.73 (s, 3H), 2.72 – 2.45 (m, 3H), 2.02 – 1.80 (m, 3H), 1.80 – 1.63 (m, 2H), 1.55 – 1.39 (m, 3H), 1.09 (d, J = 6.3 Hz, 3H), 1.01 (s, 3H). ESI MS [M+H] ⁺ for C ₃₆ H ₃₇ N ₆ , calculated 553.3, found 553.3. Example 72 : 6- methyl -2-(4-{5-[(7 S )-7-{3- oxa -6- azabicyclo [3.1.1] hept -6- yl }-6,7 ,8,9- tetrahydro -5 H -benzo [7] annen -2- yl ]-1 H -pyrrolo [2,3- b ] pyridin -3- yl } phenyl ) pyridine -3- methyl Nitrile

The title compound was prepared in an analogous manner to Example 1 from appropriate starting materials. ¹ H NMR (400 MHz, chloroform- d ) δ 10.27 (s, 1H), 8.64 (d, J = 2.0 Hz, 1H), 8.45 (d, J = 2.0 Hz, 1H), 8.10 – 8.00 (m, 2H ), 7.97 (d, J = 8.0 Hz, 1H), 7.88 – 7.82 (m, 2H), 7.66 (d, J = 2.5 Hz, 1H), 7.45 – 7.35 (m, 2H), 7.24 (d, J = 7.9 Hz, 2H), 4.32 (d, J = 10.7 Hz, 2H), 3.74 (d, J = 10.7 Hz, 2H), 3.66 (d, J = 6.1 Hz, 2H), 3.27 (t, J = 9.6 Hz , 1H), 3.01 (ddd, J = 22.5, 14.4, 8.0 Hz, 2H), 2.86 (q, J = 14.1 Hz, 2H), 2.72 (s, 3H), 2.57 (q, J = 6.7 Hz, 1H) , 2.02 – 1.89 (m, 2H), 1.85 (d, J = 8.2 Hz, 1H), 1.35 (p, J = 10.6 Hz, 2H). ESI MS [M+H] ⁺ for C ₃₆ H ₃₄ N ₅ O, calculated 552.3, found 552.3. Example 73 : 6-[( 7S )-2-{3-[4-(2,6- dimethylpyridin -3- yl ) phenyl ] -1H - pyrrolo [2,3- b ] pyridine -5- yl }-6,7,8,9 - tetrahydro - 5H - benzo [7] annen -7- yl ]-3- oxa -6- azabicyclo [3.1.1] heptane

The title compound was prepared in an analogous manner to Example 1 from appropriate starting materials. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.04 (d, J = 2.5 Hz, 1H), 8.55 (d, J = 2.1 Hz, 1H), 8.45 (d, J = 2.1 Hz, 1H), 7.98 (d, J = 2.7 Hz, 1H), 7.92 – 7.80 (m, 2H), 7.60 – 7.52 (m, 2H), 7.52 – 7.41 (m, 3H), 7.22 (d, J = 7.8 Hz, 1H), 7.17 (d, J = 7.8 Hz, 1H), 4.15 (d, J = 10.6 Hz, 2H), 3.58 (d, J = 10.6 Hz, 2H), 3.54 (d, J = 6.0 Hz, 2H), 3.17 ( t, J = 10.2 Hz, 1H), 2.96 (ddd, J = 33.1, 14.0, 8.5 Hz, 2H), 2.78 (q, J = 14.4 Hz, 2H), 2.48 (s, 3H), 2.47 (s, 3H ), 2.36 (q, J = 6.9 Hz, 1H), 1.93 – 1.79 (m, 2H), 1.68 (d, J = 7.9 Hz, 1H), 1.26 – 1.04 (m, 2H). ESI MS [M+H] ⁺ for C ₃₆ H ₃₇ N ₄ O, calculated 541.3, found 541.3. Example 74 : 6-[( 7S )-2-{3-[4-(2- methylpyridin -3- yl ) phenyl ] -1H - pyrrolo [2,3- b ] pyridine -5- yl }-6,7,8,9- tetrahydro - 5H - benzo [7] annen -7- yl ]-3- oxa -6- azabicyclo [3.1.1] heptane

The title compound was prepared in an analogous manner to Example 1 from appropriate starting materials. ¹ H NMR (400 MHz, chloroform- d ) δ 9.25 (s, 1H), 8.61 (d, J = 2.0 Hz, 1H), 8.53 (dd, J = 5.0, 1.7 Hz, 1H), 8.43 (d, J = 2.0 Hz, 1H), 7.81 – 7.72 (m, 2H), 7.62 – 7.54 (m, 2H), 7.48 – 7.42 (m, 2H), 7.42 – 7.36 (m, 2H), 7.24 – 7.18 (m, 2H ), 4.31 (d, J = 10.7 Hz, 2H), 3.73 (d, J = 10.7 Hz, 2H), 3.65 (d, J = 6.1 Hz, 2H), 3.32 – 3.19 (m, 1H), 2.99 (td , J = 15.8, 15.3, 9.5 Hz, 2H), 2.85 (q, J = 13.3 Hz, 2H), 2.60 (s, 3H), 2.59 – 2.51 (m, 1H), 2.01 – 1.88 (m, 2H), 1.85 (d, J = 8.3 Hz, 1H), 1.39 – 1.26 (m, 2H). ESI MS [M+H] ⁺ for C ₃₅ H ₃₅ N ₄ O, calculated 527.3, found 527.2. Example 75 : 5- methyl -6-(4-{5-[(7 S )-7-{3- oxa -6- azabicyclo [3.1.1] hept -6- yl }-6,7 ,8,9- tetrahydro -5 H -benzo [7] annen -2- yl ]-1 H -pyrrolo [2,3- b ] pyridin -3- yl } phenyl ) pyridine -2- methyl Nitrile

The title compound was prepared in an analogous manner to Example 1 from appropriate starting materials. ¹ H NMR (400 MHz, chloroform- d ) δ 10.30 (s, 1H), 8.64 (d, J = 2.0 Hz, 1H), 8.44 (d, J = 2.0 Hz, 1H), 7.84 – 7.77 (m, 2H ), 7.78 – 7.71 (m, 1H), 7.70 – 7.62 (m, 3H), 7.60 (d, J = 7.8 Hz, 1H), 7.45 – 7.37 (m, 2H), 7.23 (d, J = 8.2 Hz, 1H), 4.32 (d, J = 10.7 Hz, 2H), 3.74 (d, J = 10.7 Hz, 2H), 3.66 (d, J = 6.1 Hz, 2H), 3.27 (t, J = 9.7 Hz, 1H) , 3.00 (td, J = 18.6, 16.5, 7.8 Hz, 2H), 2.86 (q, J = 13.5 Hz, 2H), 2.58 (q, J = 5.8, 4.6 Hz, 1H), 2.54 (s, 3H), 2.03 – 1.89 (m, 2H), 1.85 (d, J = 8.2 Hz, 1H), 1.35 (p, J = 10.2 Hz, 2H). ESI MS [M+H] ⁺ for C ₃₆ H ₃₄ N ₅ O, calculated 552.3, found 552.3. Example 76 : 5- methyl -6-(4-{5-[(7 S )-7-{3- oxa -6- azabicyclo [3.1.1] hept -6- yl }-6,7 ,8,9- tetrahydro -5 H -benzo [7] annen -2- yl ]-1 H -pyrrolo [2,3- b ] pyridin -3- yl } phenyl ) pyridine -2- methyl amide

Step a : During the preparation of Example 75, the _title compound (see Example 1, Step g). ¹ H NMR (400 MHz, chloroform- d ) δ 10.27 (s, 1H), 8.63 (d, J = 2.0 Hz, 1H), 8.45 (d, J = 2.0 Hz, 1H), 8.12 (d, J = 7.8 Hz, 1H), 7.96 (d, J = 4.6 Hz, 1H), 7.85 – 7.74 (m, 3H), 7.70 – 7.66 (m, 2H), 7.65 (d, J = 2.5 Hz, 1H), 7.46 – 7.37 (m, 2H), 7.23 (d, J = 8.2 Hz, 1H), 5.82 (d, J = 4.6 Hz, 1H), 4.31 (d, J = 10.6 Hz, 2H), 3.73 (d, J = 10.7 Hz , 2H), 3.65 (d, J = 6.1 Hz, 2H), 3.34 – 3.19 (m, 1H), 2.99 (td, J = 15.1, 7.8 Hz, 2H), 2.86 (q, J = 13.4 Hz, 2H) , 2.56 (q, J = 6.8 Hz, 1H), 2.52 (s, 3H), 2.03 – 1.88 (m, 2H), 1.85 (d, J = 8.2 Hz, 1H), 1.33 (p, J = 10.0 Hz, 2H). ESI MS [M+H] ⁺ for C ₃₆ H ₃₆ N ₅ O ₂ , calculated 570.3, found 570.3. Example 77 : 6-[( 7S )-2-{3-[4-(4,6- dimethylpyridazin- 3- yl ) phenyl ] -1H - pyrazolo [3,4- b ] pyridin -5- yl }-6,7,8,9 - tetrahydro - 5H - benzo [7] annen -7- yl ]-3- oxa -6- azabicyclo [3.1.1] Heptane

The title compound (citrate salt) was prepared in an analogous manner to Example 2 from appropriate starting materials. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 13.91 (s, 1H), 8.90 (d, J = 2.0 Hz, 1H), 8.77 (d, J = 2.1 Hz, 1H), 8.27 (d, J = 8.3 Hz, 2H), 7.78 (d, J = 8.4 Hz, 2H), 7.69 (s, 1H), 7.63 (d, J = 7.7 Hz, 1H), 7.56 (s, 1H), 7.31 (d, J = 7.7 Hz, 1H), 4.38 – 4.07 (m, 3H), 4.00 – 3.78 (m, 2H), 3.70 – 3.60 (m, 1H), 3.49 – 3.18 (m, 3H), 3.08 – 2.80 (m, 4H) , 2.64 (s, 3H), 2.62 (d, J = 15.5 Hz, 2H), 2.53 (d, J = 16.0 Hz, 2H), 2.38 (s, 3H), 2.18 – 1.90 (m, 2H), 1.29 – 1.12 (m, 2H). ESI MS [M+H] ⁺ for C ₃₄ H ₃₅ N ₆ O, calculated 543.3, found 543.3. Example 78 : 4,6- dimethyl -3-(4-{5-[(7 S )-7- methyl -7-[(2 R )-2- methylpyrrolidin -1- yl ]- 6,7,8,9- tetrahydro - 5H - benzo [7] annen -2- yl ] -1H - pyrazolo [3,4- b ] pyridin -3- yl } phenyl ) da Azine

The title compound (citrate salt) was prepared in an analogous manner to Example 2 from appropriate starting materials. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 14.00 (s, 1H), 8.90 (d, J = 2.0 Hz, 1H), 8.75 (d, J = 2.1 Hz, 1H), 8.27 (d, J = 8.4 Hz, 2H), 7.79 (d, J = 8.4 Hz, 2H), 7.72 (s, 1H), 7.65 (d, J = 7.7 Hz, 1H), 7.56 (s, 1H), 7.33 (d, J = 7.8 Hz, 1H), 3.34 (s, 4H), 3.04 – 2.75 (m, 4H), 2.65 (s, 3H), 2.57 (d, J = 15.2 Hz, 2H), 2.49 (d, J = 14.9 Hz, 2H), 2.38 (s, 3H), 2.23 – 2.11 (m, 1H), 2.11 – 1.99 (m, 1H), 1.99 – 1.83 (m, 3H), 1.83 – 1.73 (m, 1H), 1.73 – 1.59 ( m, 2H), 1.59 – 1.40 (m, 2H), 1.26 (d, J = 6.5 Hz, 3H). ESI MS [M+H] ⁺ for C ₃₅ H ₃₉ N ₆ , calculated 543.3, found 543.3. Example 79 : 6-[( 7S )-2-{3-[1-(3- methylpyridin -2- yl ) -1H - pyrazol -4- yl ] -1H - pyrazolo [3 ,4- b ] pyridin -5- yl }-6,7,8,9 - tetrahydro -5 H -benzo [7] annen -7- yl ]-3- oxa -6- azabicyclo [ 3.1.1] Heptane

The title compound (citrate salt) was prepared in an analogous manner to Example 27 from appropriate starting materials. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 13.73 (s, 1H), 9.10 (d, J = 0.8 Hz, 1H), 8.87 (d, J = 2.0 Hz, 1H), 8.75 (d, J = 2.1 Hz, 1H), 8.49 (d, J = 0.8 Hz, 1H), 8.44 (dd, J = 4.8, 1.1 Hz, 1H), 7.95 (dd, J = 7.5, 1.0 Hz, 1H), 7.69 (s, 1H), 7.64 (d, J = 7.7 Hz, 1H), 7.45 (dd, J = 7.6, 4.8 Hz, 1H), 7.29 (d, J = 7.8 Hz, 1H), 4.40 – 4.07 (m, 3H), 3.99 – 3.79 (m, 2H), 3.74 – 3.54 (m, 1H), 3.50 – 3.20 (m, 3H), 3.07 – 2.81 (m, 4H), 2.62 (d, J = 15.2 Hz, 2H), 2.54 ( d, J = 12.6 Hz, 2H), 2.51 (s, 3H), 2.04 (t, J = 17.5 Hz, 2H), 1.20 (d, J = 16.8 Hz, 2H). ESI MS [M+H] ⁺ for C ₃₁ H ₃₂ N ₇ O, calculated 518.3, found 518.3. Example 80 : 6-[( 7S )-2-{3-[4-(4,6- dimethylpyridazin- 3- yl ) phenyl ] -1H - pyrrolo [2,3- b ] Pyridin -5- yl }-6,7,8,9 - tetrahydro - 5H - benzo [7] annen -7- yl ]-3- oxa -6- azabicyclo [3.1.1] heptan alkyl

The title compound (citrate salt) was prepared in an analogous manner to Example 1 from appropriate starting materials. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.10 (d, J = 2.7 Hz, 1H), 8.58 (d, J = 2.1 Hz, 1H), 8.50 (d, J = 2.1 Hz, 1H), 8.05 (d, J = 2.7 Hz, 1H), 7.95 (d, J = 8.3 Hz, 2H), 7.70 (d, J = 8.3 Hz, 2H), 7.61 (s, 1H), 7.55 (d, J = 7.3 Hz , 1H), 7.53 (s, 1H), 7.28 (d, J = 7.7 Hz, 1H), 4.39 – 4.07 (m, 3H), 4.00 – 3.78 (m, 2H), 3.76 – 3.55 (m, 1H), 3.48 – 3.18 (m, 3H), 3.08 – 2.78 (m, 4H), 2.63 (s, 3H), 2.61 (d, J = 14.8 Hz, 2H), 2.53 (d, J = 14.9 Hz, 2H), 2.38 (s, 3H), 2.18 – 1.93 (m, 2H), 1.30 – 1.09 (m, 2H). ESI MS [M+H] ⁺ for C ₃₅ H ₃₆ N ₅ O, calculated 542.3, found 542.3. Example 81 : 6-[( 7S )-2-{3-[3-(3- methylpyridin -2- yl ) phenyl ] -1H - pyrazolo [3,4- b ] pyridine -5 -yl } -6,7,8,9 - tetrahydro - 5H - benzo [7] annen -7- yl ]-3- oxa -6- azabicyclo [3.1.1] heptane

The title compound (citrate salt) was prepared in an analogous manner to Example 2 from appropriate starting materials. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 13.93 (s, 1H), 8.88 (d, J = 2.0 Hz, 1H), 8.67 (d, J = 2.1 Hz, 1H), 8.53 (ddd, J = 4.8, 1.7, 0.7 Hz, 1H), 8.23 – 8.20 (m, 1H), 8.17 (dt, J = 7.0, 1.9 Hz, 1H), 7.77 (ddd, J = 7.7, 1.7, 0.8 Hz, 1H), 7.69 – 7.61 (m, 3H), 7.59 (d, J = 7.8 Hz, 1H), 7.34 (dd, J = 7.7, 4.7 Hz, 1H), 7.30 (d, J = 7.8 Hz, 1H), 4.38 – 4.03 ( m, 3H), 4.00 – 3.77 (m, 2H), 3.72 – 3.53 (m, 1H), 3.45 – 3.22 (m, 3H), 3.05 – 2.82 (m, 4H), 2.61 (d, J = 15.2 Hz, 2H), 2.53 (d, J = 15.0 Hz, 2H), 2.43 (s, 3H), 2.14 – 1.93 (m, 2H), 1.29 – 1.11 (m, 2H). ESI MS [M+H] ⁺ for C ₃₄ H ₃₄ N ₅ O, calculated 528.3, found 528.3. Example 82 : 6-[( 7S )-2-{3-[3-(3- methylpyridin -2- yl ) phenyl ] -1H - pyrrolo [2,3- b ] pyridine -5- yl }-6,7,8,9- tetrahydro - 5H - benzo [7] annen -7- yl ]-3- oxa -6- azabicyclo [3.1.1] heptane

The title compound (citrate salt) was prepared in an analogous manner to Example 1 from appropriate starting materials. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.03 (d, J = 2.7 Hz, 1H), 8.56 (d, J = 2.0 Hz, 1H), 8.51 (dd, J = 4.7, 1.0 Hz, 1H) , 8.41 (d, J = 2.1 Hz, 1H), 7.97 (d, J = 2.6 Hz, 1H), 7.90 – 7.87 (m, 1H), 7.85 (dt, J = 7.7, 1.4 Hz, 1H), 7.75 ( dd, J = 7.7, 0.9 Hz, 1H), 7.61 – 7.53 (m, 2H), 7.50 (d, J = 7.0 Hz, 1H), 7.44 (dt, J = 7.6, 1.4 Hz, 1H), 7.32 (dd , J = 7.7, 4.7 Hz, 1H), 7.27 (d, J = 7.8 Hz, 1H), 4.39 – 4.07 (m, 3H), 4.00 – 3.79 (m, 2H), 3.72 – 3.55 (m, 1H), 3.47 – 3.22 (m, 3H), 3.04 – 2.81 (m, 4H), 2.61 (d, J = 15.2 Hz, 2H), 2.53 (d, J = 14.4 Hz, 2H), 2.43 (s, 3H), 2.16 – 1.91 (m, 2H), 1.33 – 1.10 (m, 2H). ESI MS [M+H] ⁺ for C ₃₅ H ₃₅ N ₄ O, calculated 527.3, found 527.3. Example 83 : 3- methyl -2'-{5-[(7 S )-7-{3- oxa -6- azabicyclo [3.1.1] hept -6- yl }-6,7,8 ,9- tetrahydro -5 H -benzo [7] annen -2- yl ]-1 H -pyrrolo [2,3- b ] pyridin -3- yl }-2,4'- bipyridine

The title compound (citrate salt) was prepared in an analogous manner to Example 9 from appropriate starting materials. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.15 (d, J = 2.6 Hz, 1H), 9.03 (d, J = 2.2 Hz, 1H), 8.73 (dd, J = 5.1, 0.9 Hz, 1H) , 8.59 – 8.54 (m, 2H), 8.41 (d, J = 2.8 Hz, 1H), 8.07 – 8.05 (m, 1H), 7.82 (dd, J = 7.8, 0.9 Hz, 1H), 7.55 (s, 1H ), 7.48 (d, J = 7.6 Hz, 1H), 7.41 (dd, J = 7.7, 4.7 Hz, 1H), 7.35 – 7.28 (m, 2H), 4.41 – 4.12 (m, 3H), 4.03 – 3.81 ( m, 2H), 3.76 – 3.58 (m, 1H), 3.49 – 3.21 (m, 3H), 3.07 – 2.83 (m, 4H), 2.62 (d, J = 15.2 Hz, 2H), 2.53 (d, J = 17.0 Hz, 2H), 2.42 (s, 3H), 2.17 – 1.96 (m, 2H), 1.29 – 1.12 (m, 2H). ESI MS [M+H] ⁺ for C ₃₄ H ₃₄ N ₅ O, calculated 528.3, found 528.3. Example 84 : 6-[(7 S )-2-(3-{2'- fluoro -6'- methyl- [1,1'- biphenyl ]-4- yl }-1 H -pyrrolo [ 2,3- b ] pyridin -5- yl )-6,7,8,9 - tetrahydro -5 H -benzo [7] annen -7- yl ]-3- oxa -6- azabicyclo [3.1.1] Heptane

The title compound (citrate salt) was prepared in an analogous manner to Example 1 from appropriate starting materials. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.06 (d, J = 2.7 Hz, 1H), 8.57 (d, J = 2.1 Hz, 1H), 8.48 (d, J = 2.1 Hz, 1H), 8.01 (d, J = 2.6 Hz, 1H), 7.90 (d, J = 8.2 Hz, 2H), 7.61 (s, 1H), 7.54 (d, J = 8.2 Hz, 1H), 7.37 (d, J = 7.7 Hz , 2H), 7.36 – 7.24 (m, 2H), 7.19 (d, J = 7.7 Hz, 1H), 7.14 (t, J = 9.0 Hz, 1H), 4.39 – 4.08 (m, 3H), 4.01 – 3.78 ( m, 2H), 3.72 – 3.58 (m, 1H), 3.48 – 3.21 (m, 3H), 3.06 – 2.81 (m, 4H), 2.61 (d, J = 15.2 Hz, 2H), 2.53 (d, J = 14.7 Hz, 2H), 2.21 (s, 3H), 2.16 – 1.93 (m, 2H), 1.28 – 1.11 (m, 2H). ESI MS [M+H] ⁺ for C ₃₆ H ₃₅ FN ₃ O, calculated value 544.3, found value 544.3. Example 85 : 2- Methyl -2-[2-[4-[5-[(7 S )-7-(3- oxa- 6- azabicyclo [3.1.1] hept -6- yl )- 6,7,8,9- tetrahydro - 5H - benzo [7] annen -3- yl ] -1H - pyrazolo [3,4- b ] pyridin - 3- yl ] phenyl ] pyridine -3- yl ] propionitrile

The title compound was prepared in an analogous manner to Example 21 from appropriate starting materials. ¹ H NMR (400 MHz, chloroform- d ) δ 11.62 (s, 1H), 8.83 (d, J = 2.1 Hz, 1H), 8.64 (dd, J = 4.7, 1.6 Hz, 1H), 8.50 (d, J = 2.1 Hz, 1H), 8.12-8.09 (m, 2H), 8.03 (dd, J = 8.2, 1.6 Hz, 1H), 7.59-7.56 (m, 2H), 7.39-7.36 (m, 3H), 7.24- 7.22 (m, 1H), 4.31 (d, J = 10.8 Hz, 2H), 3.77-3.68 (m, 4H), 3.3-3.25 (m, 1H), 2.99 (td, J = 15.4, 7.7 Hz, 2H) , 2.90-2.80 (m, 2H), 2.62-2.56 (m, 1H), 1.95 (s, 2H), 1.85 (d, 1H), 1.67 (s, 6H), 1.40-1.33 (m, 2H). ESI MS [M+H] ⁺ for C ₃₇ H ₃₇ N ₆ O, calculated 581.3, found 581.3. Example 86 : 6-[( 7S )-3-[3-[4-(4- methoxy -3- methylpyridin -2- yl ) phenyl ] -1H - pyrrolo [2,3- b ] pyridin -5- yl ]-6,7,8,9 - tetrahydro - 5H - benzo [7] annen -7- yl ]-3- oxa -6- azabicyclo [3.1.1 ] Heptane

The title compound was prepared in an analogous manner to Example 1 from appropriate starting materials. ¹ H NMR (400 MHz, chloroform- d ) δ 10.48 (s, 1H), 8.59 (s, 1H), 8.46 (d, J = 5.6 Hz, 1H), 8.41 (s, 1H), 7.77-7.68 (m , 2H), 7.63-7.57 (m, 2H), 7.55 (s, 1H), 7.42-7.34 (m, 2H), 7.19 (d, J = 7.5 Hz, 1H), 6.76 (d, J = 5.6 Hz, 1H), 4.32 (d, J = 11.1 Hz, 2H), 3.92 (s, 3H), 3.79-3.77 (m, 4H), 3.34-3.23 (m, 1H), 3.02-2.68 (m, 5H), 2.25 (s, 3H), 1.95 (s, 2H), 1.87 (d, J = 8.5 Hz, 1H), 1.47-1.37 (m, 2H). ESI MS [M+H] ⁺ for C ₃₆ H ₃₇ N ₄ O ₂ , calculated 557.3, found 557.3. Example 87 : 6-[( 7S )-3-[3-[4-(4- methoxy -3- methylpyridin -2- yl ) phenyl ] -1H - pyrazolo [3,4 - b ] pyridin -5- yl ]-6,7,8,9 - tetrahydro -5 H -benzo [7] annen -7- yl ]-3- oxa -6- azabicyclo [3.1. 1] Heptane

The title compound was prepared in an analogous manner to Example 2 from appropriate starting materials. ¹ H NMR (400 MHz, chloroform- d ) δ 11.26 (s, 1H), 8.83 (d, J = 2.0 Hz, 1H), 8.50 (d, J = 2.0 Hz, 1H), 8.45 (d, J = 5.7 Hz, 1H), 8.08-8.05 (m, 2H), 7.69-7.66 (m, 2H), 7.41-7.376 (m, 2H), 7.24-7.22 (m, 1H), 6.78 (d, J = 5.7 Hz, 1H), 4.35 (d, J = 11.4 Hz, 2H), 3.96-3.78 (m, 6H), 3.35 (s, 1H), 3.04-2.68 (m, 6H), 2.24 (s, 3H), 2.02-1.89 (m, 3H), 1.48 (s, 2H). ESI MS [M+H] ⁺ for C ₃₅ H ₃₆ N ₅ O ₂ , calculated 558.3, found 558.3. Example 88 : 6-[( 7S )-3-[3-[4-[3-( trifluoromethyl ) pyridin -2- yl ] phenyl ] -1H - pyrazolo [3,4- b ] pyridin -5- yl ]-6,7,8,9 - tetrahydro - 5H - benzo [7] annen -7- yl ]-3- oxa -6- azabicyclo [3.1.1] Heptane

The title compound was prepared in an analogous manner to Example 2 from appropriate starting materials. ¹ H NMR (400 MHz, chloroform- d ) δ 12.94 (s, 1H), 8.87-8.84 (m, 2H), 8.51 (d, J = 2.1 Hz, 1H), 8.12-8.02 (m, 3H), 7.68 (d, J = 8.2 Hz, 2H), 7.45-7.42 (m, 1H), 7.39-7.37 (m, 2H), 7.22 (d, J = 8.2 Hz, 1H), 4.31 (d, J = 10.7 Hz, 2H), 3.77-3.67 (m, 4H), 3.27 (t, J = 9.7 Hz, 1H), 3.13-2.80 (m, 4H), 2.60 (q, J = 6.7 Hz, 1H), 1.99-1.91 (m , 2H), 1.85 (d, J = 8.3 Hz, 1H), 1.39 (q, J = 11.4 Hz, 2H). ESI MS [M+H] ⁺ for C ₃₄ H ₃₁ F ₃ N ₅ O, calculated 582.2, found 582.3. Example 89 : 6-[( 7S )-3-[3-[4-[3-( difluoromethyl ) pyridin -2- yl ] phenyl ] -1H - pyrazolo [3,4- b ] pyridin -5- yl ]-6,7,8,9 - tetrahydro - 5H - benzo [7] annen -7- yl ]-3- oxa -6- azabicyclo [3.1.1] Heptane

The title compound was prepared in an analogous manner to Example 2 from appropriate starting materials. ¹ H NMR (400 MHz, chloroform- d ) δ 12.05 (s, 1H), 8.85 (d, J = 2.1 Hz, 1H), 8.83 (m, J = 5.0 Hz, 1H), 8.51 (d, J = 2.1 Hz, 1H), 8.17-8.13 (m, 3H), 7.76-7.72 (m, 2H), 7.45 (dd, J = 7.9, 4.8 Hz, 1H), 7.41-7.37 (m, 2H), 7.24-7.23 ( m, 1H), 6.72 (t, J = 54.3 Hz, 1H), 4.33 (d, J = 11.0 Hz, 2H), 3.87-3.74 (m, 4H), 3.30 (t, J = 10.3 Hz, 1H), 3.11-2.80 (m, 4H), 2.66 (s, 1H), 2.02-1.92 (m, 2H), 1.89 (d, J = 8.6 Hz, 1H), 1.49-1.38 (m, 2H). ESI MS [M+H] ⁺ for C ₃₄ H ₃₂ F ₂ N ₅ O, calculated 564.3, found 564.3. Example 90 : 2-(4-{5-[(7 S )-7- methyl- 7-[(2 R )-2- methylpyrrolidin -1- yl ]-6,7,8,9- Tetrahydro -5 H -benzo [7] annen -2- yl ]-2 H -pyrazolo [3,4- b ] pyridin -3- yl } phenyl )-1,3- oxazole

The title compound was prepared in an analogous manner to Example 2 from appropriate starting materials. ¹ H NMR (400 MHz, chloroform- d ) δ 11.37 (s, 1H), 8.86 (d, J = 2.0 Hz, 1H), 8.50 (d, J = 2.0 Hz, 1H), 8.26 – 8.17 (m, 2H ), 8.17 – 8.06 (m, 2H), 7.75 (d, J = 0.8 Hz, 1H), 7.36 (dt, J = 3.8, 2.2 Hz, 2H), 7.28 (d, J = 0.8 Hz, 1H), 7.23 (td, J = 0.4 Hz, 1H), 3.41 (s, 1H), 3.32 – 3.15 (m, 2H), 2.91 (t, J = 7.6 Hz, 1H), 2.72 – 2.45 (m, 4H), 2.00 – 1.81 (m, 3H), 1.71 (tt, J = 12.2, 6.4 Hz, 2H), 1.51 – 1.38 (m, 2H), 1.07 (d, J = 6.3 Hz, 3H), 0.98 (s, 3H). ESI MS [M+H] ⁺ for C ₃₂ H ₃₄ N ₅ O, calculated 504.3, found 504.3. Example 91 : 2-(4-{5-[(7 S )-7- methyl- 7-[(2 R )-2- methylpyrrolidin -1- yl ]-6,7,8,9- Tetrahydro - 5H - benzo [7] annen -2- yl ] -2H - pyrazolo [3,4- b ] pyridin -3- yl } phenyl )-1,3- thiazole:

The title compound was prepared in an analogous manner to Example 2 from appropriate starting materials. ¹ H NMR (400 MHz, chloroform- d ) δ 11.30 (s, 1H), 8.86 (d, J = 2.0 Hz, 1H), 8.50 (d, J = 2.1 Hz, 1H), 8.16 – 8.05 (m, 4H ), 7.90 (d, J = 3.3 Hz, 1H), 7.38 – 7.32 (m, 3H), 7.24 – 7.19 (m, 1H), 3.46-3.41(m, 1H), 3.24 (d, J = 10.4 Hz, 2H), 2.90 (d, J = 7.9 Hz, 2H), 2.68 – 2.5 (m, 3H), 1.95-1.87 (m, 3H), 1.74 – 1.71 (m, 2H), 1.50 – 1.41 (m, 2H) , 1.07 (d, J = 6.3 Hz, 3H), 0.99 (s, 3H). ESI MS [M+H] ⁺ for C ₃₂ H ₃₄ N ₅ S, calculated 520.3, found 520.3. Example 92 : N , N - dimethyl -4'-{5-[(7 S )-7-{3- oxa -6- azabicyclo [3.1.1] hept -6- yl }-6, 7,8,9- tetrahydro - 5 H -benzo [7] annen -2- yl ]-1 H -pyrrolo [2,3- b ] pyridin -3- yl }-[ 1,1'- Biphenyl ]-2- methamide:

The title compound was prepared in an analogous manner to Example 1 from appropriate starting materials. ¹ H NMR (400 MHz, chloroform- d ) δ 9.24 (s, 1H), 8.58 (d, J = 2.1 Hz, 1H), 8.40 (d, J = 2.0 Hz, 1H), 7.74 – 7.67 (m, 2H ), 7.60 – 7.53 (m, 3H), 7.48 – 7.44 (m, 2H), 7.44 – 7.36 (m, 3H), 7.23 – 7.15 (m, 2H), 4.29 (d, J = 10.7 Hz, 2H), 3.71 (d, J = 10.8 Hz, 2H), 3.63 (d, J = 6.1 Hz, 2H), 3.27-3.22 (m, 1H), 3.07 – 2.93 (m, 2H), 2.90 (s, 3H), 2.54 (d, J = 7.1 Hz, 1H), 2.49 (s, 3H), 1.93 (d, J = 11.2 Hz, 2H), 1.83 (d, J = 8.2 Hz, 1H), 1.43 – 1.10 (m, 2H) , 0.91 – 0.75 (m, 2H). ESI MS [M+H] ⁺ for C ₃₈ H ₃₉ N ₄ O ₂ , calculated 583.3, found 584.3. Example 93 : 6-[( 7S )-2-(3-{2'- methanesulfonyl- [1,1'- biphenyl ]-4- yl } -1H - pyrrolo [2,3 - b ] pyridin -5- yl )-6,7,8,9- tetrahydro -5 H -benzo [7] annen -7- yl ]-3- oxa -6- azabicyclo [3.1. 1] Heptane

The title compound was prepared in an analogous manner to Example 1 from appropriate starting materials. ¹ H NMR (400 MHz, chloroform- d ) δ 10.00 (s, 1H), 8.58 (s, 1H), 8.42 (d, J = 1.8 Hz, 1H), 8.25 (dd, J = 8.0, 1.4 Hz, 1H ), 7.83 – 7.75 (m, 2H), 7.68 – 7.62 (m, 2H), 7.61 – 7.54 (m, 2H), 7.44-7.40 (m, 2H), 7.21 (d, J = 7.7 Hz, 1H), 4.39 (d, J = 12.0 Hz, 2H), 4.27 (s, 2H), 3.99 (d, J = 12.0 Hz, 2H), 3.44 (t, J = 11.1 Hz, 1H), 3.03 – 2.79(m, 4H ), 2.72 (s, 3H), 2.03-1.99 (m, 2H), 1.62-1.56 (m, 1H), 1.33 – 1.21 (m, 2H), 0.94 (d, J = 6.6 Hz, 1H), 0.90 – 0.80 (m, 2H). ESI MS [M+H] ⁺ for C ₃₆ H ₃₆ N ₃ O ₃ S, calculated 590.25, found 590.3. Example 94 : N , N - dimethyl -6-(4-{5-[(7 S )-7-{3- oxa -6- azabicyclo [3.1.1] hept -6- yl }- 6,7,8,9- tetrahydro - 5 H -benzo [7] annen -2- yl ] -2 H -pyrazolo [3,4- b ] pyridin - 3- yl } phenyl ) pyridine -2- methamide

The title compound was prepared in an analogous manner to Example 2 from appropriate starting materials. ¹ H NMR (400 MHz, chloroform- d ) δ 11.87 (s, 1H), 8.84 (d, J = 2.0 Hz, 1H), 8.51 (d, J = 2.0 Hz, 1H), 8.19 (d, J = 8.5 Hz, 2H), 8.16 – 8.08 (m, 2H), 7.92 – 7.81 (m, 2H), 7.62 (dd, J = 7.2, 1.4 Hz, 1H), 7.38 (d, J = 6.8 Hz, 2H), 7.24 (s, 1H), 4.31 (d, J = 10.8 Hz, 2H), 3.74 (dd, J = 17.0, 8.3 Hz, 3H), 3.28 (t, J = 9.8 Hz, 1H), 3.22 (s, 3H) , 3.18 (s, 3H), 3.01-2.81 (m, 3H), 1.96-1.93 (m, 2H), 1.86 (d, J = 8.4 Hz, 2H), 1.46 – 1.31 (m, 2H), 1.31 – 1.15 (m, 1H), 0.90 – 0.81 (m, 1H). ESI MS [M+H] ⁺ for C ₃₆ H ₃₇ N ₆ O ₂ , calculated 585.3, found 585.3. Example 95 : 2-[2-(4-{5-[(7 S )-7-{3- oxa -6- azabicyclo [3.1.1] hept -6- yl }-6,7,8 ,9- tetrahydro -5 H -benzo [7] annen -2- yl ]-1 H -pyrrolo [2,3- b ] pyridin -3- yl } phenyl ) pyridin -3- yl ] propan -2- ol

The title compound was prepared in an analogous manner to Example 1 from appropriate starting materials. ¹ H NMR (400 MHz, chloroform- d ) δ 9.41 (s, 1H), 8.59 (d, J = 2.1 Hz, 1H), 8.56 (dd, J = 4.7, 1.6 Hz, 1H), 8.40 – 8.37 (m , 1H), 8.02 (dd, J = 8.1, 1.7 Hz, 1H), 7.75 – 7.68 (m, 2H), 7.52 (d, J = 2.5 Hz, 1H), 7.49 – 7.45 (m, 2H), 7.38 ( dq, J = 4.2, 2.0 Hz, 2H), 7.30 (dd, J = 8.1, 4.7 Hz, 1H), 7.20 (d, J = 8.3 Hz, 1H), 4.29 (d, J = 10.7 Hz, 2H), 3.71 (d, J = 10.7 Hz, 2H), 3.63 (d, J = 6.1 Hz, 2H), 3.23 (d, J = 9.9 Hz, 1H), 2.98 (ddd, J = 21.6, 14.5, 8.0 Hz, 2H ), 2.83 (q, J = 13.7 Hz, 2H), 2.54 (d, J = 7.2 Hz, 1H), 1.93 (brs, 2H), 1.83 (d, J = 8.2 Hz, 1H), 1.54 (s, 6H ), 1.41 – 1.20 (m, 2H), 0.95 (d, J = 6.6 Hz, 1H). ESI MS [M+H] ⁺ for C ₃₇ H ₃₉ N ₄ O ₂ , calculated 571.3, found 571.3. Example 96 : 3- methyl -6'-{5-[(7 S )-7-{3- oxa -6- azabicyclo [3.1.1] hept -6- yl }-6,7,8 ,9- tetrahydro -5 H -benzo [7] annen -2- yl ]-1 H -pyrrolo [2,3- b ] pyridin -3- yl }-2,3'- bipyridine

The title compound was prepared in an analogous manner to Example 9 from appropriate starting materials. ¹ H NMR (400 MHz, chloroform- d ) δ 10.16 (s, 1H), 8.92 (d, J = 2.1 Hz, 1H), 8.87 (dt, J = 2.4, 0.8 Hz, 1H), 8.61 (d, J = 2.1 Hz, 1H), 8.59 – 8.55 (m, 1H), 7.98 (d, J = 2.5 Hz, 1H), 7.95 (ddd, J = 8.1, 2.3, 0.6 Hz, 1H), 7.78 (dt, J = 8.2, 0.8 Hz, 1H), 7.62 (ddt, J = 7.7, 1.6, 0.8 Hz, 1H), 7.43 (dq, J = 4.6, 2.0 Hz, 2H), 7.24 – 7.17 (m, 2H), 4.30 (d , J = 10.7 Hz, 2H), 3.72 (d, J = 10.7 Hz, 2H), 3.63 (d, J = 6.1 Hz, 2H), 3.31 – 3.19 (m, 1H), 2.98 (ddd, J = 21.3, 14.3, 7.8 Hz, 2H), 2.85 (q, J = 13.7 Hz, 2H), 2.54 (q, J = 6.8 Hz, 1H), 2.46 (s, 3H), 1.94(brs, 2H), 1.83(d, J = 8.2 Hz, 1H), 1.37 – 1.24 (m, 2H). ESI MS [M+H] ⁺ for C ₃₄ H ₃₄ N ₅ O, calculated 528.3, found 528.3. Example 97 : 6-[( 7S )-2-{3-[5-(2- methylphenyl ) pyridin -2- yl ] -1H - pyrrolo [2,3- b ] pyridine -5- yl }-6,7,8,9- tetrahydro - 5H - benzo [7] annen -7- yl ]-3- oxa -6- azabicyclo [3.1.1] heptane

The title compound was prepared in an analogous manner to Example 9 from appropriate starting materials. ¹ H NMR (400 MHz, chloroform- d ) δ 9.82 (s, 1H), 8.90 (d, J = 2.1 Hz, 2H), 8.66 (dd, J = 2.3, 0.8 Hz, 1H), 8.60 (d, J = 2.1 Hz, 1H), 7.97 (d, J = 2.5 Hz, 1H), 7.75 (dd, J = 8.2, 0.9 Hz, 1H), 7.69 (dd, J = 8.1, 2.3 Hz, 1H), 7.43 (dq , J = 4.6, 2.1 Hz, 2H), 7.33 – 7.26 (m, 3H), 7.21 (d, J = 8.2 Hz, 1H), 4.30 (d, J = 10.7 Hz, 2H), 3.72 (d, J = 10.7 Hz, 2H), 3.64 (d, J = 6.1 Hz, 2H), 3.24 (t, J = 9.6 Hz, 1H), 3.07 – 2.77 (m, 3H), 2.54 (q, J = 6.8 Hz, 1H) , 2.35 (s, 3H), 1.94 (s, 2H), 1.83 (d, J = 8.3 Hz, 1H), 1.42 – 1.22 (m, 2H), 0.91 – 0.77 (m, 1H). ESI MS [M+H] ⁺ for C ₃₅ H ₃₅ N ₄ O, calculated 527.3, found 527.3. Example 98 : 6-[( 7S )-2-{3-[5-(2- methylphenyl ) pyridin -2- yl ] -1H - pyrazolo [3,4- b ] pyridine -5 -yl } -6,7,8,9 - tetrahydro - 5H - benzo [7] annen -7- yl ]-3- oxa -6- azabicyclo [3.1.1] heptane

The title compound was prepared in an analogous manner to Example 9 from appropriate starting materials. ¹ H NMR (400 MHz, chloroform-d) δ 9.85 (s, 1H), 8.90 (d, J = 2.0 Hz, 1H), 8.66 (dt, J = 2.0, 0.9 Hz, 1H), 8.60 (d, J = 2.0 Hz, 1H), 8.01 – 7.94 (m, 1H), 7.78 – 7.67 (m, 2H), 7.46 – 7.39 (m, 2H), 7.35 – 7.26 (m, 3H), 7.21 (d, J = 8.2 Hz, 1H), 4.30 (d, J = 10.6 Hz, 2H), 3.72 (d, J = 10.7 Hz, 2H), 3.63 (d, J = 6.1 Hz, 2H), 3.24 (t, J = 9.6 Hz, 1H), 3.08 – 2.77 (m, 4H), 2.57 (s, 1H), 2.35 (s, 3H), 1.94 (s, 2H), 1.40 – 1.16 (m, 3H). ESI MS [M+H] ⁺ for C ₃₄ H ₃₄ N ₅ O, calculated 528.3, found 528.3. Example 99 : 6-[(7 S )-2-(3-{4-[3-( difluoromethoxy ) pyridin -2- yl ] phenyl }-1 H -pyrazolo [3,4- b ] pyridin -5- yl )-6,7,8,9- tetrahydro - 5H - benzo [7] annen -7- yl ]-3- oxa -6- azabicyclo [3.1.1 ] Heptane

The title compound was prepared in an analogous manner to Example 2 from appropriate starting materials. ¹ H NMR (400 MHz, chloroform- d ) δ 11.48 (s, 1H), 8.84 (d, J = 2.0 Hz, 1H), 8.61 (dd, J = 4.6, 1.4 Hz, 1H), 8.52 (d, J = 2.0 Hz, 1H), 8.17 – 8.08 (m, 2H), 8.08 – 7.99 (m, 2H), 7.63 (dd, J = 8.3, 1.2 Hz, 1H), 7.39 (d, J = 7.3 Hz, 2H) , 7.31 (dd, J = 8.3, 4.6 Hz, 1H), 7.23 (dq, J = 0.4 Hz, 1H), 6.45 (t, J = 73.1 Hz, 1H), 4.32 (d, J = 11.0 Hz, 2H) , 3.78 (d, J = 10.9 Hz, 2H), 3.30 (s, 1H), 2.99 (td, J = 14.8, 7.7 Hz, 2H), 2.85 (q, J = 13.1 Hz, 2H), 2.64 (brs, 2H), 1.96 (brs, 2H), 1.88 (d, J = 8.5 Hz, 1H), 1.41 (brs, 3H). ESI MS [M+H] ⁺ for C ₃₄ H ₃₂ F ₂ N ₅ O ₂ , calculated 580.3, found 580.3. Example 100 : 2-(6'-{5-[(7 S )-7-{3- oxa -6- azabicyclo [3.1.1] hept -6- yl }-6,7,8,9 -Tetrahydro - 5 H -benzo [7] annen -2- yl ]-1 H -pyrazolo [3,4- b ] pyridin -3- yl }-[2,3'- bipyridyl ]- 3- yl ) propan -2- ol

The title compound was prepared in an analogous manner to Example 9 from appropriate starting materials. ¹ H NMR (400 MHz, chloroform- d ) δ 9.13 (d, J = 2.0 Hz, 1H), 8.82 (s, 1H), 8.75 (s, 1H), 8.58 (dd, J = 4.7, 1.6 Hz, 1H ), 8.24 (d, J = 8.1 Hz, 1H), 8.07 (dd, J = 8.2, 1.6 Hz, 1H), 7.83 (d, J = 8.1 Hz, 1H), 7.42 (dt, J = 4.5, 2.3 Hz , 1H), 7.34 (dd, J = 8.2, 4.7 Hz, 1H), 7.21 (d, J = 8.2 Hz, 1H), 4.30 (d, J = 10.6 Hz, 2H), 3.72 (d, J = 10.7 Hz , 2H), 3.64 (d, J = 6.1 Hz, 2H), 3.25 (s, 1H), 3.06 – 2.73 (m, 4H), 2.56 (d, J = 7.1 Hz, 1H), 1.93 (s, 2H) , 1.83 (d, J = 8.2 Hz, 2H), 1.52 (s, 6H), 1.42 – 1.27 (m, 3H), 0.93 – 0.68 (m, 1H). ESI MS [M+H] ⁺ for C ₃₅ H ₃₇ N ₆ O ₂ , calculated 573.3, found 573.3. Example 101 : 6-[( 7S )-2-{3-[4-(3- methanesulfonylpyridin- 2- yl ) phenyl ] -1H - pyrazolo [3,4- b ] pyridine -5- yl }-6,7,8,9 - tetrahydro - 5H - benzo [7] annen -7- yl ]-3- oxa -6- azabicyclo [3.1.1] heptane

The title compound was prepared in an analogous manner to Example 2 from appropriate starting materials. ¹ H NMR (400 MHz, chloroform- d ) δ 11.64 (s, 1H), 8.92 (ddd, J = 4.8, 1.8, 0.9 Hz, 1H), 8.85 (dd, J = 2.1, 0.9 Hz, 1H), 8.59 (ddd, J = 8.0, 1.7, 0.9 Hz, 1H), 8.53 (dd, J = 2.0, 0.9 Hz, 1H), 8.20 – 8.12 (m, 2H), 7.93 – 7.84 (m, 2H), 7.55 (ddd , J = 8.2, 4.8, 0.9 Hz, 1H), 7.39 (d, J = 6.2 Hz, 2H), 7.24 (d, J = 1.0 Hz, 1H), 4.31 (d, J = 10.8 Hz, 2H), 3.75 (d, J = 10.8 Hz, 2H), 3.69 (s, 2H), 3.27 (s, 1H), 3.09 – 2.93 (m, 2H), 2.89 (d, J = 13.6 Hz, 2H), 2.75 (s, 3H), 2.59 (d, J = 7.5 Hz, 1H), 1.95 (s, 2H), 1.85 (d, J = 8.3 Hz, 1H), 1.41 – 1.34 (m, 1H), 0.94 – 0.72 (m, 1H ). ESI MS [M+H] ⁺ for C ₃₄ H ₃₄ N ₅ O ₃ S, calculated 592.3, found 592.3. Example 102 : 6-[( 7S )-2-{3-[4-(3- methanesulfonylpyridin- 2- yl ) phenyl ] -1H - pyrrolo [2,3- b ] pyridine- 5- yl }-6,7,8,9 - tetrahydro - 5H - benzo [7] annen -7- yl ]-3- oxa -6- azabicyclo [3.1.1] heptane

The title compound was prepared in an analogous manner to Example 1 from appropriate starting materials. ¹ H NMR (400 MHz, chloroform- d ) δ 9.99 (s, 1H), 8.91 (dd, J = 4.8, 1.7 Hz, 1H), 8.61 (d, J = 2.1 Hz, 1H), 8.58 (dd, J = 8.1, 1.7 Hz, 1H), 8.43 (d, J = 2.0 Hz, 1H), 7.87 – 7.76 (m, 4H), 7.64 (d, J = 2.4 Hz, 1H), 7.53 (dd, J = 8.1, 4.8 Hz, 1H), 7.39 (dt, J = 4.3, 2.0 Hz, 2H), 7.21 (d, J = 8.2 Hz, 1H), 4.30 (d, J = 10.7 Hz, 2H), 3.72 (d, J = 10.7 Hz, 2H), 3.64 (d, J = 6.1 Hz, 2H), 3.30 – 3.18 (m, 1H), 2.98 (ddd, J = 22.5, 14.5, 7.9 Hz, 2H), 2.84 (q, J = 14.6 Hz, 2H), 2.77 (s, 3H), 2.55 (q, J = 6.8 Hz, 1H), 1.94 (d, J = 11.8 Hz, 2H), 1.84 (s, 1H), 1.39 – 1.21 (m, 2H ). ESI MS [M+H] ⁺ for C ₃₅ H ₃₅ N ₄ O ₃ S, calculated 591.3, found 591.3. Example 103 : 6-[( 7S )-2-(3-{4-[3-( trifluoromethoxy ) pyridin -2- yl ] phenyl } -1H - pyrrolo [2,3- b ] pyridin -5- yl )-6,7,8,9- tetrahydro - 5H - benzo [7] annen -7- yl ]-3- oxa -6- azabicyclo [3.1.1] Heptane

The title compound was prepared in an analogous manner to Example 1 from appropriate starting materials. ¹ H NMR (400 MHz, chloroform- d ) δ 9.76 (s, 1H), 8.66 (dd, J = 4.6, 1.4 Hz, 1H), 8.58 (d, J = 1.9 Hz, 1H), 8.44 (d, J = 1.9 Hz, 1H), 8.00 – 7.92 (m, 2H), 7.82 – 7.76 (m, 2H), 7.69 (dt, J = 8.3, 1.5 Hz, 1H), 7.62 (d, J = 2.0 Hz, 1H) , 7.42 – 7.37 (m, 2H), 7.32 (dd, J = 8.3, 4.6 Hz, 1H), 7.21 (d, J = 8.3 Hz, 1H), 4.30 (d, J = 10.8 Hz, 2H), 3.76 – 3.63 (m, 4H), 3.25 (t, J = 9.6 Hz, 1H), 2.98 (td, J = 17.4, 16.2, 7.8 Hz, 2H), 2.83 (q, J = 13.2 Hz, 2H), 2.57 (d , J = 7.6 Hz, 1H), 1.94 (s, 2H), 1.83 (d, J = 8.3 Hz, 1H), 1.44 – 1.25 (m, 2H). ESI MS [M+H] ⁺ for C ₃₅ H ₃₂ F ₃ N ₄ O ₂ , calculated 597.3, found 597.3. Example 104 : 6-[(7 S )-2-[3-(4-{3-[(3 R ) -oxolane- 3- yloxy ] pyridin -2- yl } phenyl )-1 H -Pyrazolo [3,4- b ] pyridin -5- yl ]-6,7,8,9 - tetrahydro -5 H -benzo [7] annen -7- yl ] -3 - oxa- 6- Azabicyclo [3.1.1] heptane

The title compound was prepared in an analogous manner to Example 2 from appropriate starting materials. ¹ H NMR (400 MHz, chloroform- d ) δ 11.84 (s, 1H), 8.84 (d, J = 2.0 Hz, 1H), 8.53 (d, J = 2.0 Hz, 1H), 8.37 (dd, J = 3.7 , 2.2 Hz, 1H), 8.18 – 8.02 (m, 3H), 7.39 (d, J = 6.8 Hz, 2H), 7.26 – 7.21 (m, 3H), 7.08 (s, 1H), 5.02 – 4.91 (m, 1H), 4.31 (d, J = 10.8 Hz, 2H), 4.02 (d, J = 3.3 Hz, 2H), 4.00 – 3.87 (m, 2H), 3.82 – 3.65 (m, 4H), 3.28 (s, 1H ), 2.99 (td, J = 15.1, 7.9 Hz, 2H), 2.85 (q, J = 13.8, 13.3 Hz, 2H), 2.60 (s, 2H), 2.24 – 2.15 (m, 2H), 1.95 (s, 2H), 1.47 – 1.28 (m, 2H). ESI MS [M+H] ⁺ for C ₃₇ H ₃₈ N ₅ O ₃ , calculated 600.3, found 600.3. Example 105 : 3- methyl -6'-{5-[(7 S )-7- methyl -7-[(2 R )-2- methylpyrrolidin -1- yl ]-6,7,8 ,9- tetrahydro -5 H -benzo [7] annen -2- yl ]-1 H -pyrazolo [3,4- b ] pyridin -3- yl }-2,3'- bipyridine

The title compound was prepared in an analogous manner to Example 9 from appropriate starting materials. ¹ H NMR (400 MHz, chloroform- d ) δ 11.5 (s, 1H), 9.18 (d, J = 2.0 Hz, 1H), 8.94 (dd, J = 2.3, 0.8 Hz, 1H), 8.87 (s, 1H ), 8.62 – 8.56 (m, 1H), 8.31 (dd, J = 8.2, 0.8 Hz, 1H), 8.03 (dd, J = 8.1, 2.2 Hz, 1H), 7.67 – 7.62 (m, 1H), 7.45 – 7.39 (m, 2H), 7.25 (d, J = 4.4 Hz, 1H), 7.23 – 7.19 (m, 1H), 3.39 (s, 1H), 3.30 – 3.18 (m, 2H), 2.91 (t, J = 7.6 Hz, 1H), 2.71 – 2.47 (m, 3H), 2.46 (s, 3H), 2.00 – 1.77 (m, 3H), 1.77 – 1.38 (m, 8H), 1.07 (d, J = 6.3 Hz, 3H ). ESI MS [M+H] ⁺ for C ₃₄ H ₃₇ N ₆ , calculated 529.3, found 529.3. Example 106 : (3 S ) -N -[(7 S )-2-(3-{3- methyl- [2,3'- bipyridin ]-6'- yl }-1 H -pyrazolo [ 3,4- b ] pyridin -5- yl )-6,7,8,9 - tetrahydro -5 H -benzo [7] annen -7- yl ] oxane -3- amine

The title compound was prepared in an analogous manner to Example 9 from appropriate starting materials. ¹ H NMR (400 MHz, chloroform-d) δ 11.55 (s, 1H), 9.18 (d, J = 2.2 Hz, 1H), 8.95 (dd, J = 2.3, 0.8 Hz, 1H), 8.85 (d, J = 2.1 Hz, 1H), 8.59 (ddd, J = 4.8, 1.6, 0.7 Hz, 1H), 8.32 (dd, J = 8.2, 0.9 Hz, 1H), 8.03 (dd, J = 8.2, 2.3 Hz, 1H) , 7.64 (ddd, J = 7.7, 1.7, 0.7 Hz, 1H), 7.49 – 7.41 (m, 2H), 7.26-7.22 (m, 2H), 4.52 (s, 1H), 4.15 (d, J = 9.1 Hz , 1H), 3.79 (d, J = 9.0 Hz, 2H), 3.08 (d, J = 16.2 Hz, 3H), 2.93 – 2.68 (m, 2H), 2.46 (s, 2H), 2.16 (brs, 3H) , 2.00 (d, J = 21.3 Hz, 1H), 1.55 (dd, J = 91.0, 45.9 Hz, 6H), 1.26 (d, J = 7.9 Hz, 1H). ESI MS [M+H] ⁺ for C ₃₃ H ₃₅ N ₆ O, calculated 531.3, found 531.3. Example 107 : (3 S ) -N -[(7 S )-2-(3-{3- methyl- [2,3'- bipyridin ]-6'- yl }-1 H -pyrazolo [ 3,4- b ] pyridin -5- yl )-6,7,8,9 - tetrahydro -5 H -benzo [7] annen -7- yl ] oxane -3- amine

The title compound was prepared in an analogous manner to Example 9 from appropriate starting materials. ¹ H NMR (400 MHz, chloroform- d ) δ 11.75 (s, 1H), 9.14 (d, J = 2.2 Hz, 1H), 8.92 (dd, J = 2.2, 0.8 Hz, 1H), 8.82 (d, J = 2.1 Hz, 1H), 8.64 – 8.53 (m, 1H), 8.29 (dd, J = 8.1, 0.8 Hz, 1H), 8.01 (dd, J = 8.2, 2.2 Hz, 1H), 7.63 (ddd, J = 7.7, 1.7, 0.8 Hz, 1H), 7.47 – 7.34 (m, 2H), 7.26 – 7.18 (m, 2H), 4.00 – 3.88 (m, 1H), 3.80 (dt, J = 11.3, 4.0 Hz, 1H) , 3.48 – 3.35 (m, 1H), 3.25 (t, J = 9.9 Hz, 1H), 2.93 (ddd, J = 22.4, 15.0, 8.3 Hz, 3H), 2.78 (q, J = 14.5 Hz, 2H), 2.45 (s, 3H), 2.19-1.98 (m, 2H), 1.99 (d, J = 12.6 Hz, 1H), 1.83 – 1.57 (m, 3H), 1.42 (d, J = 13.7 Hz, 2H). ESI MS [M+H] ⁺ for C ₃₃ H ₃₃ N ₆ O, calculated 529.3, found 529.3. Example 108 : (7 S )-2-(3-{3- methyl- [ 2,3'- bipyridin ]-6'- yl }-1 H -pyrazolo [3,4- b ] pyridine- 5- yl ) -N- [ cis -3- methoxycyclobutyl ]-6,7,8,9 - tetrahydro - 5H - benzo [7] annen -7- amine

The title compound was prepared in an analogous manner to Example 9 from appropriate starting materials. ¹ H NMR (400 MHz, chloroform- d ) δ 9.06 (d, J = 2.2 Hz, 1H), 8.90 (dd, J = 2.2, 0.8 Hz, 1H), 8.72 (d, J = 2.2 Hz, 1H), 8.58 (dd, J = 4.8, 1.6 Hz, 1H), 8.25 (dd, J = 8.2, 0.9 Hz, 1H), 7.98 (dd, J = 8.2, 2.2 Hz, 1H), 7.67 – 7.60 (m, 1H) , 7.35 (dd, J = 5.4, 2.1 Hz, 2H), 7.24 – 7.14 (m, 3H), 3.66 (t, J = 7.0 Hz, 2H), 3.25 (t, J = 7.9 Hz, 1H), 3.21 ( s, 3H), 3.17 – 3.04 (m, 1H), 2.93 (td, J = 14.2, 7.6 Hz, 2H), 2.83 – 2.57 (m, 4H), 2.43 (s, 2H), 2.25 (s, 2H) , 2.10 (d, J = 9.3 Hz, 2H), 2.06 (s, 2H), 1.70 – 1.42 (m, 1H). ESI MS [M+H] ⁺ for C ₃₃ H ₃₅ N ₆ O, calculated 531.3, found 531.3. Example 109 : 6-[( 7S )-2-{3-[4-(1- methyl - 1H - pyrazol -5- yl ) phenyl ] -1H - pyrazolo [3,4- b ] Pyridin -5- yl }-6,7,8,9 - tetrahydro - 5H - benzo [7] annen -7- yl ]-3- oxa -6- azabicyclo [3.1.1 ] Heptane

The title compound was prepared in an analogous manner to Example 2 from appropriate starting materials. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 13.93 (s, 1H), 8.84 (d, J = 2.1 Hz, 1H), 8.69 (d, J = 2.1 Hz, 1H), 8.25 – 8.17 (m, 2H), 7.70 – 7.64 (m, 2H), 7.58 (d, J = 2.0 Hz, 1H), 7.52 (dd, J = 7.7, 2.0 Hz, 1H), 7.47 (d, J = 1.9 Hz, 1H), 7.22 (d, J = 7.8 Hz, 1H), 6.46 (d, J = 1.9 Hz, 1H), 4.12 (d, J = 10.6 Hz, 2H), 3.90 (s, 3H), 3.53 (dd, J = 18.0 , 8.3 Hz, 4H), 3.18 – 3.09 (m, 1H), 3.04 – 2.86 (m, 2H), 2.83 – 2.66 (m, 2H), 2.32 (q, J = 6.9 Hz, 1H), 1.90 – 1.75 ( m, 2H), 1.64 (d, J = 7.9 Hz, 1H), 1.30 – 1.03 (m, 2H). ESI MS [M+H] ⁺ for C ₃₂ H ₃₃ N ₆ O, calculated 517.3, found 517.3. Example 110 : 6-[( 7S )-2-{3-[4-(1- methyl - 1H -1,2,4- triazol -5- yl ) phenyl ] -2H - pyrazole And [3,4- b ] pyridin -5- yl }-6,7,8,9 - tetrahydro -5 H -benzo [7] annen -7- yl ]-3- oxa -6- nitrogen Heterobicyclo [3.1.1] heptane

The title compound was prepared in an analogous manner to Example 2 from appropriate starting materials. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 14.00 (s, 1H), 8.85 (d, J = 2.1 Hz, 1H), 8.72 (d, J = 2.0 Hz, 1H), 8.32 – 8.24 (m, 2H), 8.01 (s, 1H), 7.97 – 7.88 (m, 2H), 7.59 (d, J = 2.0 Hz, 1H), 7.53 (dd, J = 7.7, 2.0 Hz, 1H), 7.22 (d, J = 7.7 Hz, 1H), 4.12 (d, J = 10.6 Hz, 2H), 4.02 (s, 3H), 3.53 (dd, J = 18.4, 8.3 Hz, 4H), 3.19 – 3.10 (m, 1H), 3.05 – 2.86 (m, 2H), 2.83 – 2.68 (m, 2H), 2.39 – 2.26 (m, 1H), 1.90 – 1.75 (m, 2H), 1.64 (d, J = 7.9 Hz, 1H), 1.27 – 1.06 (m, 2H). ESI MS [M+H] ⁺ for C ₃₁ H ₃₂ N ₇ O, calculated 518.3, found 518.2. Example 111 : 6-[( 7S )-2-{3-[4-(1- methyl - 1H - imidazol -2- yl ) phenyl ] -1H - pyrazolo [3,4- b ] pyridin -5- yl }-6,7,8,9 - tetrahydro - 5H - benzo [7] annen -7- yl ]-3- oxa -6- azabicyclo [3.1.1] Heptane

The title compound was prepared in an analogous manner to Example 2 from appropriate starting materials. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 13.92 (s, 1H), 8.84 (d, J = 2.0 Hz, 1H), 8.70 (d, J = 2.1 Hz, 1H), 8.19 (d, J = 8.4 Hz, 2H), 7.84 (d, J = 8.5 Hz, 2H), 7.59 (d, J = 1.9 Hz, 1H), 7.52 (dd, J = 7.7, 2.0 Hz, 1H), 7.27 (d, J = 1.1 Hz, 1H), 7.22 (d, J = 7.8 Hz, 1H), 6.99 (d, J = 1.1 Hz, 1H), 4.12 (d, J = 10.6 Hz, 2H), 3.80 (s, 3H), 3.53 (dd, J = 17.8, 8.3 Hz, 4H), 3.18 – 3.07 (m, 1H), 3.04 – 2.84 (m, 2H), 2.84 – 2.67 (m, 2H), 2.39 – 2.24 (m, 1H), 1.89 – 1.74 (m, 2H), 1.64 (d, J = 7.9 Hz, 1H), 1.25 – 1.03 (m, 2H). ESI MS [M+H] ⁺ for C ₃₂ H ₃₃ N ₆ O, calculated 517.3, found 517.3. Example 112 : 1- Methyl- 5-(4-{5-[(7 S )-7- methyl -7-[(2 R )-2- methylpyrrolidin -1- yl ]-6,7 ,8,9- tetrahydro -5 H -benzo [7] annen -2- yl ]-1 H -pyrazolo [3,4- b ] pyridin -3- yl } phenyl )-1 H - 1,2,4- triazole

The title compound was prepared in an analogous manner to Example 18 from appropriate starting materials. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 13.99 (s, 1H), 8.84 (d, J = 2.1 Hz, 1H), 8.70 (d, J = 2.1 Hz, 1H), 8.38 – 8.21 (m, 2H), 8.01 (s, 1H), 7.95 – 7.89 (m, 2H), 7.55 (d, J = 2.0 Hz, 1H), 7.50 (dd, J = 7.7, 2.0 Hz, 1H), 7.20 (d, J = 7.8 Hz, 1H), 4.02 (s, 3H), 3.40 – 3.10 (m, 3H), 2.80 (t, J = 7.4 Hz, 1H), 2.69 – 2.39 (m, 3H), 1.91 – 1.79 (m, 2H), 1.79 – 1.72 (m, 1H), 1.71 – 1.56 (m, 2H), 1.46 – 1.14 (m, 3H), 1.00 (d, J = 6.2 Hz, 3H), 0.89 (s, 3H). ESI MS [M+H] ⁺ for C ₃₂ H ₃₆ N ₇ , calculated 518.3, found 518.3. Example 113 : 2-[2-(5-{5-[(7 S )-7-{3- oxa -6- azabicyclo [3.1.1] hept -6- yl }-6,7,8 ,9- tetrahydro -5 H -benzo [7] annen -2- yl ]-1 H -pyrazolo [3,4- b ] pyridin - 3- yl } pyridin -2- yl ) phenyl ] Propan -2- ol

The title compound was prepared in an analogous manner to Example 10 from appropriate starting materials. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.32 (dd, J = 2.4, 0.9 Hz, 1H), 8.87 (d, J = 2.1 Hz, 1H), 8.78 (d, J = 2.0 Hz, 1H) , 8.60 (dd, J = 8.2, 2.3 Hz, 1H), 7.68 (dd, J = 7.8, 1.4 Hz, 1H), 7.65 – 7.60 (m, 2H), 7.55 (dd, J = 7.6, 2.0 Hz, 1H ), 7.41 (td, J = 7.6, 1.7 Hz, 1H), 7.34 (td, J = 7.4, 1.3 Hz, 1H), 7.28 (dd, J = 7.6, 1.6 Hz, 1H), 7.22 (d, J = 7.8 Hz, 1H), 6.05 (s, 1H), 4.12 (d, J = 10.6 Hz, 2H), 3.60 – 3.46 (m, 4H), 3.19 – 3.11 (m, 1H), 3.04 – 2.85 (m, 2H ), 2.84 – 2.66 (m, 2H), 2.38 – 2.26 (m, 1H), 1.89 – 1.74 (m, 2H), 1.65 (d, J = 7.9 Hz, 1H), 1.31 (s, 6H), 1.25 – 1.07 (m, 2H). ESI MS [M+H] ⁺ for C ₃₆ H ₃₈ N ₅ O ₂ , calculated 572.3, found 572.3. Example 114 : 2-[2-(5-{5-[(7 S )-7-{3- oxa -6- azabicyclo [3.1.1] hept -6- yl }-6,7,8 ,9- tetrahydro -5 H -benzo [7] annen -2 -yl ]-1 H -pyrrolo [2,3- b ] pyridin - 3- yl } pyridin -2- yl ) phenyl ] propan -2- ol

The title compound was prepared in an analogous manner to Example 10 from appropriate starting materials. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.17 (d, J = 2.7 Hz, 1H), 9.06 (dd, J = 2.4, 0.8 Hz, 1H), 8.55 (d, J = 2.1 Hz, 1H) , 8.48 (d, J = 2.1 Hz, 1H), 8.37 (dd, J = 8.2, 2.4 Hz, 1H), 8.15 (d, J = 2.7 Hz, 1H), 7.66 (dd, J = 7.8, 1.4 Hz, 1H), 7.59 – 7.52 (m, 2H), 7.47 (dd, J = 7.7, 1.9 Hz, 1H), 7.41 – 7.29 (m, 3H), 7.19 (d, J = 7.8 Hz, 1H), 6.48 (s , 1H), 4.12 (d, J = 10.5 Hz, 2H), 3.59 – 3.46 (m, 4H), 3.19 – 3.08 (m, 1H), 3.04 – 2.83 (m, 2H), 2.82 – 2.67 (m, 2H ), 2.36 – 2.27 (m, 1H), 1.91 – 1.76 (m, 2H), 1.65 (d, J = 7.9 Hz, 1H), 1.30 (s, 6H), 1.25 – 1.03 (m, 2H). ESI MS [M+H] ⁺ for C ₃₇ H ₃₉ N ₄ O ₂ , calculated 571.3, found 571.3. Example 115 : 6-[( 7S )-2-{3-[4-(5- methylpyridin -2- yl ) phenyl ] -1H -pyrazolo [ 3,4- b ] pyridine -5 -yl } -6,7,8,9 - tetrahydro - 5H - benzo [7] annen -7- yl ]-3- oxa -6- azabicyclo [3.1.1] heptane

The title compound was prepared in an analogous manner to Example 1 from appropriate starting materials. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 13.91 (s, 1H), 8.84 (d, J = 2.1 Hz, 1H), 8.69 (d, J = 2.1 Hz, 1H), 8.51 (dt, J = 2.4, 0.8 Hz, 1H), 8.24 – 8.16 (m, 4H), 7.92 (d, J = 8.1 Hz, 1H), 7.70 (ddd, J = 8.1, 2.3, 0.8 Hz, 1H), 7.59 (d, J = 2.0 Hz, 1H), 7.52 (dd, J = 7.7, 2.0 Hz, 1H), 7.23 (d, J = 7.8 Hz, 1H), 4.13 (d, J = 10.6 Hz, 2H), 3.53 (dd, J = 18.0, 8.3 Hz, 4H), 3.19 – 3.09 (m, 1H), 2.95 (dt, J = 31.4, 11.1 Hz, 2H), 2.77 (q, J = 14.2 Hz, 2H), 2.36 – 2.27 (m, 4H), 1.87 – 1.76 (m, 2H), 1.65 (d, J = 7.9 Hz, 1H), 1.21 – 1.04 (m, 2H). ESI MS [M+H] ⁺ for C ₃₄ H ₃₄ N ₅ O, calculated 528.3, found 528.3. Example 116 : 6-[( 7S )-2-{3-[4-(6- methylpyridin -2- yl ) phenyl ] -1H -pyrazolo [ 3,4- b ] pyridine -5 -yl } -6,7,8,9 - tetrahydro - 5H - benzo [7] annen -7- yl ]-3- oxa -6- azabicyclo [3.1.1] heptane

The title compound was prepared in an analogous manner to Example 1 from appropriate starting materials. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 13.91 (s, 1H), 8.85 (d, J = 2.1 Hz, 1H), 8.70 (d, J = 2.1 Hz, 1H), 8.28 – 8.16 (m, 4H), 7.85 – 7.72 (m, 2H), 7.59 (d, J = 2.0 Hz, 1H), 7.53 (dd, J = 7.7, 2.0 Hz, 1H), 7.27 – 7.19 (m, 2H), 4.13 (d , J = 10.6 Hz, 2H), 3.53 (dd, J = 18.1, 8.3 Hz, 4H), 3.20 – 3.10 (m, 1H), 3.05 – 2.86 (m, 2H), 2.77 (q, J = 14.2 Hz, 2H), 2.54 (s, 3H), 2.38 – 2.27 (m, 1H), 1.90 – 1.77 (m, 2H), 1.65 (d, J = 7.8 Hz, 1H), 1.23 – 1.03 (m, 2H). ESI MS [M+H] ⁺ for C ₃₄ H ₃₄ N ₅ O, calculated 528.3, found 528.3. Example 117 : 6-[( 7S )-2-{3-[4-(4- methylpyridin -2- yl ) phenyl ] -1H -pyrazolo [ 3,4- b ] pyridine -5 -yl } -6,7,8,9 - tetrahydro - 5H - benzo [7] annen -7- yl ]-3- oxa -6- azabicyclo [3.1.1] heptane

The title compound was prepared in an analogous manner to Example 2 from appropriate starting materials. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 13.92 (s, 1H), 8.84 (d, J = 2.1 Hz, 1H), 8.69 (d, J = 2.1 Hz, 1H), 8.52 (d, J = 5.0 Hz, 1H), 8.25 – 8.18 (m, 4H), 7.87 (d, J = 1.5 Hz, 1H), 7.59 (d, J = 2.0 Hz, 1H), 7.52 (dd, J = 7.7, 2.0 Hz, 1H), 7.23 (d, J = 7.8 Hz, 1H), 7.19 (dd, J = 5.3, 1.1 Hz, 1H), 4.13 (d, J = 10.7 Hz, 2H), 3.53 (dd, J = 17.9, 8.3 Hz, 4H), 3.20 – 3.10 (m, 1H), 3.05 – 2.85 (m, 2H), 2.77 (q, J = 14.6, 14.1 Hz, 2H), 2.39 (s, 3H), 2.36 – 2.26 (m, 1H), 1.89 – 1.76 (m, 2H), 1.65 (d, J = 7.9 Hz, 1H), 1.22 – 1.01 (m, 2H). ESI MS [M+H] ⁺ for C ₃₄ H ₃₄ N ₅ O, calculated 528.3, found 528.3. Example 118 : 6-[( 7S )-2-{3-[4-(3,4- dimethylpyridin -2- yl ) phenyl ] -1H - pyrazolo [3,4- b ] Pyridin -5- yl }-6,7,8,9 - tetrahydro - 5H - benzo [7] annen -7- yl ]-3- oxa -6- azabicyclo [3.1.1] heptan alkyl

The title compound was prepared in an analogous manner to Example 2 from appropriate starting materials. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 13.89 (s, 1H), 8.84 (d, J = 2.1 Hz, 1H), 8.70 (d, J = 2.1 Hz, 1H), 8.34 (d, J = 4.8 Hz, 1H), 8.23 – 8.10 (m, 2H), 7.65 – 7.57 (m, 3H), 7.52 (dd, J = 7.7, 2.0 Hz, 1H), 7.25 – 7.17 (m, 2H), 4.12 (d , J = 10.6 Hz, 2H), 3.53 (dd, J = 18.2, 8.3 Hz, 4H), 3.19 – 3.09 (m, 1H), 3.04 – 2.84 (m, 2H), 2.76 (q, J = 13.9 Hz, 2H), 2.36 – 2.28 (m, 4H), 2.26 (s, 3H), 1.91 – 1.78 (m, 2H), 1.64 (d, J = 7.8 Hz, 1H), 1.22 – 1.01 (m, 2H). ESI MS [M+H] ⁺ for C ₃₅ H ₃₆ N ₅ O, calculated 542.3, found 542.3. Example 119 : 6-[( 7S )-2-{3-[4-(3,5- dimethylpyridin -2- yl ) phenyl ] -1H - pyrazolo [3,4- b ] Pyridin -5- yl }-6,7,8,9 - tetrahydro - 5H - benzo [7] annen -7- yl ]-3- oxa -6- azabicyclo [3.1.1] heptan alkyl

The title compound was prepared in an analogous manner to Example 2 from appropriate starting materials. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 13.89 (s, 1H), 8.84 (d, J = 2.0 Hz, 1H), 8.69 (d, J = 2.1 Hz, 1H), 8.40 – 8.30 (m, 1H), 8.21 – 8.10 (m, 2H), 7.72 – 7.64 (m, 2H), 7.59 (d, J = 2.0 Hz, 1H), 7.56 – 7.49 (m, 2H), 7.22 (d, J = 7.8 Hz , 1H), 4.12 (d, J = 10.6 Hz, 2H), 3.53 (dd, J = 18.2, 8.3 Hz, 4H), 3.19 – 3.08 (m, 1H), 3.05 – 2.84 (m, 2H), 2.76 ( q, J = 14.5, 14.0 Hz, 2H), 2.39 – 2.27 (m, 7H), 1.89 – 1.77 (m, 2H), 1.64 (d, J = 7.8 Hz, 1H), 1.21 – 1.02 (m, 2H) . ESI MS [M+H] ⁺ for C ₃₅ H ₃₆ N ₅ O, calculated 542.3, found 542.3. Example 120 : 6-[( 7S )-2-{3-[4-(3,6- dimethylpyridin -2- yl ) phenyl ] -1H - pyrazolo [3,4- b ] Pyridin -5- yl }-6,7,8,9 - tetrahydro - 5H - benzo [7] annen -7- yl ]-3- oxa -6- azabicyclo [3.1.1] heptan alkyl

The title compound was prepared in an analogous manner to Example 2 from appropriate starting materials. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 13.89 (s, 1H), 8.84 (d, J = 2.1 Hz, 1H), 8.69 (d, J = 2.1 Hz, 1H), 8.17 (d, J = 8.4 Hz, 2H), 7.70 – 7.65 (m, 2H), 7.62 – 7.57 (m, 2H), 7.52 (dd, J = 7.7, 2.0 Hz, 1H), 7.22 (d, J = 7.8 Hz, 1H), 7.15 (d, J = 7.8 Hz, 1H), 4.12 (d, J = 10.6 Hz, 2H), 3.53 (dd, J = 18.2, 8.3 Hz, 4H), 3.20 – 3.09 (m, 1H), 3.05 – 2.85 (m, 2H), 2.76 (q, J = 14.1 Hz, 2H), 2.48 – 2.44 (m, 3H), 2.37 – 2.25 (m, 4H), 1.89 – 1.76 (m, 2H), 1.64 (d, J = 7.9 Hz, 1H), 1.22 – 1.02 (m, 2H). ESI MS [M+H] ⁺ for C ₃₅ H ₃₆ N ₅ O, calculated 542.3, found 542.3. Example 121 : 3-[2-(4-{5-[(7 S )-7-{3- oxa -6- azabicyclo [3.1.1] hept -6- yl }-6,7,8 ,9- tetrahydro -5 H -benzo [7] annen -2- yl ]-1 H -pyrazolo [3,4- b ] pyridin -3- yl } phenyl ) pyridin -3- yl ] -1,3- oxazolidin -2- one

The title compound was prepared in an analogous manner to Example 7 from appropriate starting materials. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 13.93 (s, 1H), 8.84 (d, J = 2.0 Hz, 1H), 8.73 (d, J = 2.0 Hz, 1H), 8.65 (dd, J = 4.7, 1.6 Hz, 1H), 8.27 – 8.20 (m, 2H), 7.98 (dd, J = 8.0, 1.6 Hz, 1H), 7.81 – 7.72 (m, 2H), 7.59 (s, 1H), 7.56 – 7.48 (m, 2H), 7.23 (d, J = 7.8 Hz, 1H), 4.35 (dd, J = 8.8, 7.0 Hz, 2H), 4.12 (d, J = 10.6 Hz, 2H), 3.79 – 3.71 (m, 2H), 3.53 (dd, J = 17.9, 8.3 Hz, 4H), 3.19 – 3.09 (m, 1H), 3.05 – 2.85 (m, 2H), 2.77 (q, J = 14.0 Hz, 2H), 2.37 – 2.24 (m, 1H), 1.89 – 1.75 (m, 2H), 1.65 (d, J = 7.8 Hz, 1H), 1.25 – 0.98 (m, 2H). ESI MS [M+H] ⁺ for C ₃₆ H ₃₅ N ₆ O ₃ , calculated 599.3, found 599.3. Example 122 : 6-[( 7S )-2-{3-[4-(2,5- dimethylpyrimidin -4- yl ) phenyl ] -1H - pyrazolo [3,4- b ] Pyridin -5- yl }-6,7,8,9 - tetrahydro - 5H - benzo [7] annen -7- yl ]-3- oxa -6- azabicyclo [3.1.1] heptan alkyl

The title compound was prepared in an analogous manner to Example 2 from appropriate starting materials. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 13.96 (s, 1H), 8.85 (d, J = 2.0 Hz, 1H), 8.71 (d, J = 2.1 Hz, 1H), 8.61 (d, J = 0.8 Hz, 1H), 8.26 – 8.21 (m, 2H), 7.84 – 7.79 (m, 2H), 7.59 (d, J = 2.0 Hz, 1H), 7.53 (dd, J = 7.8, 2.0 Hz, 1H), 7.23 (d, J = 7.8 Hz, 1H), 4.13 (d, J = 10.6 Hz, 2H), 3.53 (dd, J = 18.8, 8.3 Hz, 4H), 3.21 – 3.10 (m, 1H), 3.05 – 2.85 (m, 2H), 2.77 (q, J = 14.3 Hz, 2H), 2.61 (s, 3H), 2.39 – 2.27 (m, 4H), 1.90 – 1.77 (m, 2H), 1.65 (d, J = 7.9 Hz, 1H), 1.27 – 1.08 (m, 2H). ESI MS [M+H] ⁺ for C ₃₄ H ₃₅ N ₆ O, calculated 543.3, found 543.3. Example 123 : 6-[(7 S )-2-{3-[4-(2,5- dimethylpyrimidin - 4- yl ) phenyl ]-1 H -pyrrolo [2,3- b ] pyridine -5- yl }-6,7,8,9 - tetrahydro - 5H - benzo [7] annen -7- yl ]-3- oxa -6- azabicyclo [3.1.1] heptane

The title compound was prepared in an analogous manner to Example 1 from appropriate starting materials. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.06 (d, J = 2.7 Hz, 1H), 8.58 (d, J = 0.8 Hz, 1H), 8.53 (d, J = 2.1 Hz, 1H), 8.45 (d, J = 2.1 Hz, 1H), 8.01 (d, J = 2.7 Hz, 1H), 7.94 – 7.89 (m, 2H), 7.77 – 7.72 (m, 2H), 7.51 (d, J = 2.0 Hz, 1H), 7.45 (dd, J = 7.7, 2.0 Hz, 1H), 7.19 (d, J = 7.8 Hz, 1H), 4.12 (d, J = 10.6 Hz, 2H), 3.53 (dd, J = 18.6, 8.3 Hz, 4H), 3.19 – 3.09 (m, 1H), 3.03 – 2.84 (m, 2H), 2.75 (q, J = 14.1 Hz, 2H), 2.60 (s, 3H), 2.38 – 2.28 (m, 4H) , 1.89 – 1.77 (m, 2H), 1.64 (d, J = 7.8 Hz, 1H), 1.27 – 1.06 (m, 2H). ESI MS [M+H] ⁺ for C ₃₅ H ₃₆ N ₅ O, calculated 542.3, found 542.3. Example 124 : (4 R )-4- methyl -3-[2-(4-{5-[(7 S )-7-{3- oxa -6- azabicyclo [3.1.1 ] hept- 6- yl }-6,7,8,9- tetrahydro -5 H -benzo [7] annen -2- yl ]-1 H -pyrazolo [3,4- b ] pyridin -3- yl } Phenyl ) pyridin -3- yl ]-1,3- oxazolidin -2- one

The title compound was prepared in an analogous manner to Example 7 from appropriate starting materials. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 13.94 (s, 1H), 8.84 (d, J = 2.1 Hz, 1H), 8.74 (d, J = 2.0 Hz, 1H), 8.68 (dd, J = 4.7, 1.6 Hz, 1H), 8.27 – 8.21 (m, 2H), 7.92 (dd, J = 8.0, 1.6 Hz, 1H), 7.77 – 7.71 (m, 2H), 7.59 (d, J = 2.0 Hz, 1H ), 7.56 – 7.49 (m, 2H), 7.23 (d, J = 7.8 Hz, 1H), 4.49 – 4.39 (m, 1H), 4.12 (d, J = 10.6 Hz, 2H), 3.94 – 3.83 (m, 2H), 3.53 (dd, J = 17.7, 8.3 Hz, 4H), 3.19 – 3.09 (m, 1H), 3.04 – 2.85 (m, 2H), 2.84 – 2.69 (m, 2H), 2.38 – 2.27 (m, 1H), 1.89 – 1.76 (m, 2H), 1.65 (d, J = 7.9 Hz, 1H), 1.28 – 1.07 (m, 2H), 0.94 – 0.87 (m, 3H). ESI MS [M+H] ⁺ for C ₃₇ H ₃₇ N ₆ O ₃ , calculated 613.3, found 613.3. Example 125 : (4 S )-4- methyl -3-[2-(4-{5-[(7 S )-7-{3- oxa -6- azabicyclo [3.1.1 ] hept- 6- yl }-6,7,8,9- tetrahydro -5 H -benzo [7] annen -2- yl ]-1 H -pyrazolo [3,4- b ] pyridin -3- yl } Phenyl ) pyridin -3- yl ]-1,3- oxazolidin -2- one

The title compound was prepared in an analogous manner to Example 7 from appropriate starting materials. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 13.94 (s, 1H), 8.84 (d, J = 2.1 Hz, 1H), 8.74 (d, J = 2.1 Hz, 1H), 8.68 (dd, J = 4.7, 1.6 Hz, 1H), 8.27 – 8.22 (m, 2H), 7.92 (dd, J = 8.1, 1.6 Hz, 1H), 7.75 – 7.71 (m, 2H), 7.59 (s, 1H), 7.52 (dt , J = 8.0, 4.5 Hz, 2H), 7.23 (d, J = 7.8 Hz, 1H), 4.53 – 4.36 (m, 1H), 4.13 (d, J = 10.6 Hz, 2H), 3.95 – 3.84 (m, 2H), 3.63 – 3.45 (m, 4H), 3.20 – 3.09 (m, 1H), 3.06 – 2.84 (m, 2H), 2.77 (q, J = 14.0 Hz, 2H), 2.39 – 2.25 (m, 1H) , 1.92 – 1.77 (m, 2H), 1.65 (d, J = 7.8 Hz, 1H), 1.28 – 1.04 (m, 2H), 0.91 (dd, J = 6.2, 1.8 Hz, 3H). ESI MS [M+H] ⁺ for C ₃₇ H ₃₇ N ₆ O ₃ , calculated 613.3, found 613.3. Example 126 : 3-[3-(4-{5-[(7 S )-7-{3- oxa -6- azabicyclo [3.1.1] hept -6- yl }-6,7,8 ,9- tetrahydro -5 H -benzo [7] annen -2- yl ]-1 H -pyrazolo [3,4- b ] pyridin -3- yl } phenyl ) pyrazin -2- yl ]-1,3- oxazolidin -2- one

The title compound was prepared in an analogous manner to Example 7 from appropriate starting materials. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.74 (s, 1H), 8.69 (dd, J = 2.5, 0.6 Hz, 1H), 8.63 (s, 1H), 8.50 (d, J = 2.4 Hz, 1H), 8.17 (d, J = 8.3 Hz, 2H), 7.88 (d, J = 8.1 Hz, 2H), 7.56 (s, 1H), 7.50 (d, J = 7.7 Hz, 1H), 7.21 (d, J = 7.8 Hz, 1H), 4.51 (t, J = 7.7 Hz, 2H), 4.26 (t, J = 7.8 Hz, 2H), 4.13 (d, J = 10.6 Hz, 2H), 3.53 (dd, J = 17.5, 8.3 Hz, 4H), 3.20 – 3.09 (m, 1H), 3.04 – 2.83 (m, 2H), 2.76 (q, J = 14.4, 14.0 Hz, 2H), 2.37 – 2.25 (m, 1H), 1.89 – 1.77 (m, 2H), 1.65 (d, J = 7.8 Hz, 1H), 1.25 – 1.01 (m, 2H). ESI MS [M+H] ⁺ for C ₃₅ H ₃₄ N ₇ O ₃ , calculated 600.3, found 600.3. Example 127 : 1-[2-(4-{5-[(7 S )-7-{3- oxa -6- azabicyclo [3.1.1] hept -6- yl }-6,7,8 ,9- tetrahydro -5 H -benzo [7] annen -2- yl ]-1 H -pyrazolo [3,4- b ] pyridin -3- yl } phenyl ) pyridin -3- yl ] Piperidin -2- one

The title compound was prepared in an analogous manner to Example 7 from appropriate starting materials. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 13.92 (s, 1H), 8.84 (d, J = 2.1 Hz, 1H), 8.71 (d, J = 2.1 Hz, 1H), 8.62 (dd, J = 4.7, 1.6 Hz, 1H), 8.25 – 8.18 (m, 2H), 7.77 (dd, J = 7.9, 1.6 Hz, 1H), 7.72 – 7.66 (m, 2H), 7.58 (d, J = 2.0 Hz, 1H ), 7.52 (dd, J = 7.7, 2.0 Hz, 1H), 7.46 (dd, J = 7.9, 4.7 Hz, 1H), 7.23 (d, J = 7.8 Hz, 1H), 4.12 (d, J = 10.6 Hz , 2H), 3.59 – 3.37 (m, 6H), 3.18 – 3.05 (m, 1H), 3.04 – 2.86 (m, 2H), 2.76 (q, J = 14.0 Hz, 2H), 2.40 – 2.21 (m, 3H ), 1.90 – 1.78 (m, 2H), 1.78 – 1.62 (m, 4H), 1.60 – 1.39 (m, 1H), 1.27 – 1.07 (m, 2H). ESI MS [M+H] ⁺ for C ₃₈ H ₃₉ N ₆ O ₂ , calculated 611.3, found 611.3. Example 128 : N - Methyl - N- [2-(4-{5-[(7 S )-7-{3- oxa -6- azabicyclo [3.1.1] hept -6- yl }- 6,7,8,9- tetrahydro -5 H -benzo [7] annen -2- yl ]-1 H -pyrazolo [3,4- b ] pyridin - 3- yl } phenyl ) pyridine -3- yl ] cyclopropanemethamide

The title compound was prepared in an analogous manner to Example 7 from appropriate starting materials. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 13.94 (s, 1H), 8.83 (d, J = 2.0 Hz, 1H), 8.73 – 8.68 (m, 2H), 8.25 – 8.19 (m, 2H), 7.96 (dd, J = 8.0, 1.6 Hz, 1H), 7.76 – 7.71 (m, 2H), 7.59 (d, J = 2.0 Hz, 1H), 7.56 – 7.50 (m, 2H), 7.22 (d, J = 7.8 Hz, 1H), 4.12 (d, J = 10.5 Hz, 2H), 3.53 (dd, J = 17.8, 8.3 Hz, 4H), 3.18 – 3.10 (m, 1H), 3.04 (s, 3H), 3.01 – 2.84 (m, 2H), 2.76 (q, J = 14.2 Hz, 2H), 2.37 – 2.26 (m, 1H), 1.92 – 1.75 (m, 2H), 1.65 (d, J = 7.9 Hz, 1H), 1.29 – 1.05 (m, 3H), 0.74 – 0.65 (m, 1H), 0.61 – 0.51 (m, 1H), 0.48 – 0.40 (m, 2H). ESI MS [M+H] ⁺ for C ₃₈ H ₃₉ N ₆ O ₂ , calculated 611.3, found 611.3. Example 129 : ( 3S ) -N -[( 7S )-2-{3-[4-(3- methylpyridin -2- yl ) phenyl ] -1H - pyrazolo [3,4- b ] pyridin -5- yl }-6,7,8,9 - tetrahydro - 5H - benzo [7]annen - 7- yl ] oxane -3- amine

The title compound was prepared in an analogous manner to Example 2 from appropriate starting materials. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 13.90 (s, 1H), 8.84 (d, J = 2.0 Hz, 1H), 8.69 (d, J = 2.1 Hz, 1H), 8.49 (ddd, J = 4.7, 1.7, 0.7 Hz, 1H), 8.21 – 8.15 (m, 2H), 7.75 – 7.68 (m, 3H), 7.59 (d, J = 2.0 Hz, 1H), 7.52 (dd, J = 7.8, 2.0 Hz , 1H), 7.30 (dd, J = 7.6, 4.7 Hz, 1H), 7.21 (d, J = 7.8 Hz, 1H), 3.76 (dd, J = 10.4, 3.8 Hz, 1H), 3.67 (d, J = 11.3 Hz, 1H), 3.20 (td, J = 10.9, 2.8 Hz, 1H), 2.93 (dd, J = 10.8, 8.9 Hz, 2H), 2.90 – 2.77 (m, 2H), 2.76 – 2.53 (m, 3H ), 2.39 (s, 3H), 1.98 – 1.82 (m, 2H), 1.60 – 1.53 (m, 1H), 1.53 – 1.39 (m, 1H), 1.27 – 1.11 (m, 4H). ESI MS [M+H] ⁺ for C ₃₄ H ₃₆ N ₅ O, calculated 530.3, found 530.3. Example 130 : (1 S ,4 S )-5-[(7 S )-2-{3-[4-(3- methylpyridin -2- yl ) phenyl ]-1 H -pyrazolo [3 ,4- b ] pyridin -5- yl }-6,7,8,9 - tetrahydro -5 H -benzo [7] annen -7- yl ]-2- oxa -5- azabicyclo [ 2.2.1] Heptane

The title compound was prepared in an analogous manner to Example 2 from appropriate starting materials. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.84 (d, J = 2.1 Hz, 1H), 8.69 (d, J = 2.1 Hz, 1H), 8.49 (ddd, J = 4.8, 1.7, 0.7 Hz, 1H), 8.22 – 8.13 (m, 2H), 7.76 – 7.67 (m, 3H), 7.58 (d, J = 2.0 Hz, 1H), 7.52 (dd, J = 7.7, 2.0 Hz, 1H), 7.29 (dd , J = 7.7, 4.7 Hz, 1H), 7.21 (d, J = 7.8 Hz, 1H), 4.31 (d, J = 2.2 Hz, 1H), 3.88 (d, J = 7.5 Hz, 1H), 3.69 (s , 1H), 3.51 (dd, J = 7.7, 1.6 Hz, 1H), 3.12 – 2.90 (m, 3H), 2.76 – 2.52 (m, 3H), 2.39 (s, 3H), 2.35 – 2.28 (m, 1H ), 1.94 – 1.74 (m, 2H), 1.70 (d, J = 9.2 Hz, 1H), 1.59 (d, J = 9.3 Hz, 1H), 1.52 – 1.39 (m, 1H), 1.27 – 1.18 (m, 2H). ESI MS [M+H] ⁺ for C ₃₄ H ₃₄ N ₅ O, calculated 528.3, found 528.2. Example 131 : ( 7S )-2-{3-[4-(3- methylpyridin -2- yl ) phenyl ] -1H - pyrazolo [3,4- b ] pyridin -5- yl } - N -[ cis -3- methoxycyclobutyl ]-6,7,8,9- tetrahydro - 5H - benzo [7] annen -7- amine

The title compound was prepared in an analogous manner to Example 2 from appropriate starting materials. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 13.90 (s, 1H), 8.83 (d, J = 2.1 Hz, 1H), 8.69 (d, J = 2.1 Hz, 1H), 8.49 (ddd, J = 4.7, 1.7, 0.7 Hz, 1H), 8.20 – 8.16 (m, 2H), 7.75 – 7.68 (m, 3H), 7.58 (d, J = 2.0 Hz, 1H), 7.52 (dd, J = 7.7, 2.0 Hz , 1H), 7.29 (dd, J = 7.7, 4.7 Hz, 1H), 7.21 (d, J = 7.8 Hz, 1H), 3.48 (p, J = 7.2 Hz, 1H), 3.07 (s, 3H), 2.98 – 2.80 (m, 3H), 2.79 – 2.57 (m, 3H), 2.39 (s, 3H), 1.98 – 1.81 (m, 2H), 1.59 – 1.43 (m, 2H), 1.31 – 1.14 (m, 4H) . ESI MS [M+H] ⁺ for C ₃₄ H ₃₆ N ₅ O, calculated 530.3, found 530.3. Example 132 : 2-(4-{5-[(7 S )-7-[(3 S )-3-( methoxymethyl ) pyrrolidin -1- yl ]-6,7,8,9- Tetrahydro -5 H -benzo [7] annen -2- yl ]-1 H -pyrazolo [3,4- b ] pyridin -3- yl } phenyl )-3- methylpyridine

The title compound was prepared in an analogous manner to Example 2 from appropriate starting materials. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 13.91 (s, 1H), 8.84 (d, J = 2.1 Hz, 1H), 8.69 (d, J = 2.1 Hz, 1H), 8.49 (ddd, J = 4.7, 1.7, 0.7 Hz, 1H), 8.21 – 8.16 (m, 2H), 7.75 – 7.68 (m, 3H), 7.58 (d, J = 2.0 Hz, 1H), 7.51 (dd, J = 7.7, 2.0 Hz , 1H), 7.29 (dd, J = 7.7, 4.7 Hz, 1H), 7.21 (d, J = 7.8 Hz, 1H), 3.23 – 3.18 (m, 5H), 3.12 – 2.97 (m, 2H), 2.69 – 2.59 (m, 2H), 2.58 – 2.51 (m, 2H), 2.39 (s, 3H), 2.35 – 2.22 (m, 3H), 1.89 – 1.75 (m, 2H), 1.71 – 1.48 (m, 2H), 1.39 – 1.31 (m, 1H), 1.26 – 1.18 (m, 2H). ESI MS [M+H] ⁺ for C ₃₅ H ₃₈ N ₅ O, calculated 544.3, found 544.3. Example 133 : 6-[( 7S )-2-{3-[4-(1- methyl - 1H -1,2,4- triazol -5- yl ) phenyl ] -1H - pyrrolo [2,3- b ] pyridin -5- yl }-6,7,8,9 - tetrahydro -5 H -benzo [7] annen -7- yl ]-3- oxa -6- aza Bicyclo [3.1.1] heptane

The title compound was prepared in an analogous manner to Example 1 from appropriate starting materials. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.09 (s, 1H), 8.53 (d, J = 2.1 Hz, 1H), 8.46 (d, J = 2.1 Hz, 1H), 8.04 (d, J = 2.7 Hz, 1H), 8.00 – 7.93 (m, 3H), 7.83 (d, J = 8.5 Hz, 2H), 7.51 (d, J = 2.0 Hz, 1H), 7.45 (dd, J = 7.6, 2.0 Hz, 1H), 7.20 (d, J = 7.8 Hz, 1H), 4.12 (d, J = 10.5 Hz, 2H), 4.00 (s, 3H), 3.53 (dd, J = 18.5, 8.3 Hz, 4H), 3.17 – 3.09 (m, 1H), 3.04 – 2.84 (m, 2H), 2.75 (q, J = 13.9 Hz, 2H), 2.38 – 2.27 (m, 1H), 1.89 – 1.77 (m, 2H), 1.64 (d, J = 7.9 Hz, 1H), 1.27 – 1.18 (m, 1H), 1.18 – 1.04 (m, 1H). ESI MS [M+H] ⁺ for C ₃₂ H ₃₃ N ₆ O, calculated 517.3, found 517.3. Example 134 : ( 3S ) -N -[( 7S )-2-{3-[4-(3- methylpyridin -2- yl ) phenyl ] -1H - pyrazolo [3,4- b ] pyridin -5- yl }-6,7,8,9 - tetrahydro - 5H - benzo [7]annen - 7- yl ] oxane -3- amine

The title compound was prepared in an analogous manner to Example 2 from appropriate starting materials. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 13.99 (s, 1H), 8.85 (d, J = 2.1 Hz, 1H), 8.72 (d, J = 2.0 Hz, 1H), 8.32 – 8.23 (m, 2H), 8.01 (d, J = 0.8 Hz, 1H), 7.98 – 7.89 (m, 2H), 7.59 (d, J = 1.9 Hz, 1H), 7.53 (dd, J = 7.8, 1.9 Hz, 1H), 7.22 (d, J = 7.8 Hz, 1H), 4.02 (s, 3H), 3.76 (d, J = 11.0 Hz, 1H), 3.67 (d, J = 11.1 Hz, 1H), 3.25 – 3.17 (m, 1H ), 3.01 – 2.78 (m, 4H), 2.78 – 2.53 (m, 3H), 2.06 – 1.81 (m, 2H), 1.64 – 1.53 (m, 1H), 1.53 – 1.38 (m, 1H), 1.32 – 1.07 (m, 4H). ESI MS [M+H] ⁺ for C ₃₁ H ₃₄ N ₇ O, calculated 520.3, found 520.3. Example 135 : (1 S ,4 S )-5-[(7 S )-2-{3-[4-(1- methyl -1 H -1,2,4- triazol -5- yl ) benzene base ] -1H - pyrazolo [3,4- b ] pyridin -5- yl }-6,7,8,9 - tetrahydro - 5H - benzo [7] annen -7- yl ]- 2- oxa -5- azabicyclo [2.2.1] heptane

The title compound was prepared in an analogous manner to Example 2 from appropriate starting materials. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 13.99 (s, 1H), 8.85 (d, J = 2.1 Hz, 1H), 8.72 (d, J = 2.0 Hz, 1H), 8.30 – 8.25 (m, 2H), 8.01 (d, J = 0.5 Hz, 1H), 7.96 – 7.90 (m, 2H), 7.59 (d, J = 2.0 Hz, 1H), 7.52 (dd, J = 7.7, 2.0 Hz, 1H), 7.22 (d, J = 7.8 Hz, 1H), 4.31 (s, 1H), 4.02 (s, 3H), 3.88 (d, J = 7.5 Hz, 1H), 3.69 (d, J = 2.1 Hz, 1H), 3.51 (d, J = 7.5 Hz, 1H), 3.11 – 2.92 (m, 3H), 2.78 – 2.54 (m, 3H), 2.35 – 2.28 (m, 1H), 1.92 – 1.76 (m, 2H), 1.70 ( d, J = 9.2 Hz, 1H), 1.59 (d, J = 9.3 Hz, 1H), 1.54 – 1.38 (m, 1H), 1.28 – 1.18 (m, 1H). ESI MS [M+H] ⁺ for C ₃₁ H ₃₂ N ₇ O, calculated 518.3, found 518.3. Example 136 : 3,6- dimethyl -2-(4-{5-[(7 S )-7- methyl -7-[(2 R )-2- methylpyrrolidin -1- yl ]- 6,7,8,9- tetrahydro -5 H -benzo [7] annen -2- yl ]-1 H -pyrazolo [3,4- b ] pyridin - 3- yl } phenyl ) pyridine

The title compound was prepared in an analogous manner to Example 18 from appropriate starting materials. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 13.87 (s, 1H), 8.80 (s, 1H), 8.65 (d, J = 2.1 Hz, 1H), 8.18 – 8.13 (m, 2H), 7.67 ( d, J = 8.3 Hz, 2H), 7.60 (d, J = 7.8 Hz, 1H), 7.54 (d, J = 1.9 Hz, 1H), 7.49 (dd, J = 7.7, 2.0 Hz, 1H), 7.19 ( d, J = 7.8 Hz, 1H), 7.14 (d, J = 7.8 Hz, 1H), 3.24 – 3.09 (m, 3H), 2.80 (t, J = 7.5 Hz, 1H), 2.67 – 2.51 (m, 3H ), 2.49 – 2.45 (m, 3H), 2.33 (s, 3H), 1.91 – 1.80 (m, 2H), 1.80 – 1.73 (m, 1H), 1.73 – 1.60 (m, 2H), 1.42 – 1.22 (m , 3H), 1.00 (d, J = 6.2 Hz, 3H), 0.90 (d, J = 3.5 Hz, 3H). ESI MS [M+H] ⁺ for C ₃₆ H ₄₀ N ₅ , calculated 542.3, found 542.3. Example 137 : 6-[( 7S )-2-{3-[4-(3,6- dimethylpyridin -2- yl ) phenyl ] -1H - pyrrolo [2,3- b ] pyridine -5- yl }-6,7,8,9 - tetrahydro - 5H - benzo [7] annen -7- yl ]-3- oxa -6- azabicyclo [3.1.1] heptane

The title compound was prepared in an analogous manner to Example 1 from appropriate starting materials. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.00 (s, 1H), 8.53 (d, J = 2.0 Hz, 1H), 8.43 (d, J = 2.1 Hz, 1H), 7.95 (d, J = 2.6 Hz, 1H), 7.87 – 7.81 (m, 2H), 7.58 (dd, J = 8.0, 6.0 Hz, 3H), 7.52 (s, 1H), 7.45 (s, 1H), 7.20 (d, J = 7.5 Hz, 1H), 7.12 (d, J = 7.7 Hz, 1H), 4.22 – 4.06 (m, 2H), 3.52 (dd, J = 18.2, 8.3 Hz, 4H), 3.19 – 3.07 (m, 1H), 3.04 – 2.66 (m, 4H), 2.48 – 2.44 (m, 3H), 2.37 – 2.27 (m, 4H), 1.89 – 1.76 (m, 2H), 1.65 (d, J = 7.9 Hz, 1H), 1.25 – 1.02 (m, 2H). ESI MS [M+H] ⁺ for C ₃₆ H ₃₇ N ₄ O, calculated 541.3, found 542.3. Example 138 : 6-[( 7S )-2-{3-[4-(1- ethyl - 1H -1,2,4- triazol -5- yl ) phenyl ] -1H - pyrazole And [3,4- b ] pyridin -5- yl }-6,7,8,9 - tetrahydro -5 H -benzo [7] annen -7- yl ]-3- oxa -6- nitrogen Heterobicyclo [3.1.1] heptane

The title compound was prepared in an analogous manner to Example 23 from appropriate starting materials. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 14.00 (s, 1H), 8.86 (d, J = 2.0 Hz, 1H), 8.73 (d, J = 2.0 Hz, 1H), 8.32 – 8.25 (m, 2H), 8.04 (s, 1H), 7.87 – 7.80 (m, 2H), 7.59 (d, J = 2.0 Hz, 1H), 7.53 (dd, J = 7.8, 2.0 Hz, 1H), 7.23 (d, J = 7.8 Hz, 1H), 4.31 (q, J = 7.2 Hz, 2H), 4.12 (d, J = 10.6 Hz, 2H), 3.53 (dd, J = 18.2, 8.3 Hz, 4H), 3.20 – 3.09 (m , 1H), 3.05 – 2.85 (m, 2H), 2.77 (q, J = 14.1 Hz, 2H), 2.38 – 2.27 (m, 1H), 1.89 – 1.76 (m, 2H), 1.65 (d, J = 7.9 Hz, 1H), 1.41 (t, J = 7.2 Hz, 3H), 1.28 – 1.09 (m, 2H). ESI MS [M+H] ⁺ for C ₃₂ H ₃₄ N ₇ O, calculated 532.3, found 532.3. Example 139 : 3,6- dimethyl -2-(4-{5-[(7 S )-7-( pyrrolidin -1- yl )-6,7,8,9- tetrahydro - 5H - Benzo [7] annen -2- yl ]-1 H -pyrazolo [3,4- b ] pyridin -3- yl } phenyl ) pyridine

The title compound was prepared in an analogous manner to Example 2 from appropriate starting materials. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 13.90 (s, 1H), 8.84 (d, J = 2.1 Hz, 1H), 8.69 (d, J = 2.0 Hz, 1H), 8.21 – 8.13 (m, 2H), 7.72 – 7.64 (m, 2H), 7.64 – 7.56 (m, 2H), 7.52 (d, J = 7.9 Hz, 1H), 7.22 (d, J = 7.7 Hz, 1H), 7.15 (d, J = 7.8 Hz, 1H), 3.19 – 2.81 (m, 5H), 2.71 – 2.49 (m, 4H), 2.49 – 2.45 (m, 3H), 2.33 (s, 3H), 1.93 – 1.45 (m, 5H), 1.35 – 1.07 (m, 3H). ESI MS [M+H] ⁺ for C ₃₄ H ₃₆ N ₅ , calculated 514.3, found 514.3. Example 140 : ( 3S ) -N -[( 7S )-2-{3-[4-(3,6- dimethylpyridin -2- yl ) phenyl ] -1H - pyrazolo [3 ,4- b ] pyridin -5- yl }-6,7,8,9 - tetrahydro -5 H -benzo [7] annen -7- yl ] oxane -3- amine

The title compound was prepared in an analogous manner to Example 2 from appropriate starting materials. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 13.89 (s, 1H), 8.84 (d, J = 2.1 Hz, 1H), 8.69 (d, J = 2.1 Hz, 1H), 8.19 – 8.14 (m, 2H), 7.70 – 7.65 (m, 2H), 7.62 – 7.57 (m, 2H), 7.52 (dd, J = 7.7, 2.0 Hz, 1H), 7.21 (d, J = 7.8 Hz, 1H), 7.15 (d , J = 7.8 Hz, 1H), 3.79 – 3.72 (m, 1H), 3.67 (dt, J = 11.0, 3.8 Hz, 1H), 3.21 (td, J = 10.8, 2.7 Hz, 1H), 2.99 – 2.90 ( m, 2H), 2.90 – 2.79 (m, 2H), 2.75 – 2.55 (m, 3H), 2.48 – 2.44 (m, 3H), 2.33 (s, 3H), 2.05 – 1.83 (m, 3H), 1.63 – 1.53 (m, 1H), 1.52 – 1.38 (m, 1H), 1.31 – 1.04 (m, 3H). ESI MS [M+H] ⁺ for C ₃₅ H ₃₈ N ₅ O, calculated 544.3, found 544.3. Example 141 : (1 S ,4 S )-5-[(7 S )-2-{3-[4-(3,6- dimethylpyridin -2- yl ) phenyl ]-1 H -pyrazole And [3,4- b ] pyridin -5- yl }-6,7,8,9 - tetrahydro -5 H -benzo [7] annen -7- yl ]-2- oxa -5- nitrogen Heterobicyclo [2.2.1] heptane

The title compound was prepared in an analogous manner to Example 2 from appropriate starting materials. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.79 (s, 1H), 8.65 (s, 1H), 8.18 – 8.13 (m, 2H), 7.68 – 7.64 (m, 2H), 7.62 – 7.55 (m , 2H), 7.50 (dd, J = 7.7, 1.9 Hz, 1H), 7.20 (d, J = 7.8 Hz, 1H), 7.14 (d, J = 7.8 Hz, 1H), 4.30 (s, 1H), 3.88 (d, J = 7.5 Hz, 1H), 3.69 (s, 1H), 3.55 – 3.47 (m, 1H), 3.09 – 2.92 (m, 3H), 2.77 – 2.67 (m, 2H), 2.65 – 2.59 (m , 1H), 2.48 – 2.45 (m, 3H), 2.33 (s, 3H), 2.31 – 2.28 (m, 1H), 1.92 – 1.75 (m, 2H), 1.70 (d, J = 9.3 Hz, 1H), 1.59 (d, J = 9.3 Hz, 1H), 1.53 – 1.37 (m, 1H), 1.28 – 1.18 (m, 1H). ESI MS [M+H] ⁺ for C ₃₅ H ₃₆ N ₅ O, calculated 542.3, found 542.3. Example 142 : 3,6- dimethyl -6'-{5-[(7 S )-7-[(1 R )-3- oxa -6- azabicyclo [3.1.1] hept -6- base ]-6,7,8,9- tetrahydro - 5H - benzo [7] annen - 2- yl ] -1H - pyrrolo [2,3- b ] pyridin -3- yl }-2 ,3'- bipyridine

The title compound was prepared in an analogous manner to Example 9 from appropriate starting materials. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.15 (s, 1H), 8.96 (d, J = 2.2 Hz, 1H), 8.78 (dd, J = 2.2, 1.0 Hz, 1H), 8.52 (d, J = 2.2 Hz, 1H), 8.34 (d, J = 2.8 Hz, 1H), 8.02 – 7.92 (m, 2H), 7.61 (d, J = 7.9 Hz, 1H), 7.47 (s, 1H), 7.41 ( d, J = 7.7 Hz, 1H), 7.21 (d, J = 7.7 Hz, 1H), 7.16 (d, J = 7.8 Hz, 1H), 4.13 (d, J = 10.6 Hz, 2H), 3.61 – 3.44 ( m, 4H), 3.22 – 3.07 (m, 1H), 3.04 – 2.85 (m, 2H), 2.84 – 2.67 (m, 2H), 2.48 – 2.45 (m, 3H), 2.38 – 2.28 (m, 4H), 1.91 – 1.75 (m, 2H), 1.65 (d, J = 7.9 Hz, 1H), 1.29 – 1.05 (m, 2H). ESI MS [M+H] ⁺ for C ₃₅ H ₃₆ N ₅ O, calculated 542.3, found 542.3. Example 143 : (1 R )-6-[(7 S )-2-{3-[4-(3,6- dimethylpyridin -2- yl )-2- fluorophenyl ]-1 H -pyra Azolo [3,4- b ] pyridin -5- yl }-6,7,8,9 - tetrahydro -5 H -benzo [7] annen -7- yl ]-3- oxa -6- Azabicyclo [3.1.1] heptane

The title compound was prepared in an analogous manner to Example 2 from appropriate starting materials. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.86 (d, J = 2.1 Hz, 1H), 8.42 (t, J = 2.7 Hz, 1H), 7.96 (t, J = 7.8 Hz, 1H), 7.63 (d, J = 7.8 Hz, 1H), 7.59 – 7.51 (m, 3H), 7.46 (d, J = 8.3 Hz, 1H), 7.20 (dd, J = 10.5, 7.8 Hz, 2H), 4.12 (d, J = 10.7 Hz, 2H), 3.57 – 3.48 (m, 4H), 3.18 – 3.06 (m, 1H), 3.02 – 2.84 (m, 2H), 2.84 – 2.67 (m, 2H), 2.48 – 2.45 (m, 3H), 2.38 – 2.28 (m, 4H), 1.89 – 1.76 (m, 2H), 1.64 (d, J = 7.7 Hz, 1H), 1.24 – 1.07 (m, 2H). ESI MS [M+H] ⁺ for C ₃₅ H ₃₅ FN ₅ O, calculated value 560.3, found value 560.3. Example 144 : (1 R )-6-[(7 S )-2-{3-[4-(3,6- dimethylpyridin -2- yl )-2- fluorophenyl ]-1 H -pyrrole And [2,3- b ] pyridin -5- yl }-6,7,8,9 - tetrahydro -5 H -benzo [7] annen -7- yl ]-3- oxa -6- nitrogen Heterobicyclo [3.1.1] heptane

The title compound was prepared in an analogous manner to Example 1 from appropriate starting materials. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.14 (d, J = 2.7 Hz, 1H), 8.55 (d, J = 2.1 Hz, 1H), 8.27 (s, 1H), 7.88 – 7.82 (m, 2H), 7.62 – 7.58 (m, 1H), 7.50 – 7.44 (m, 3H), 7.42 (d, J = 7.7 Hz, 1H), 7.17 (dd, J = 12.9, 7.8 Hz, 2H), 4.12 (d , J = 10.2 Hz, 2H), 3.60 – 3.49 (m, 4H), 3.18 – 3.08 (m, 1H), 3.02 – 2.82 (m, 2H), 2.81 – 2.69 (m, 2H), 2.48 – 2.45 (m , 3H), 2.37 – 2.27 (m, 4H), 1.90 – 1.76 (m, 2H), 1.65 (d, J = 7.7 Hz, 1H), 1.22 – 1.06 (m, 2H). ESI MS [M+H] ⁺ for C ₃₆ H ₃₆ FN ₄ O, calculated 559.3, found 559.3. Example 145 : (1 R )-6-[(7 S )-2-(3-{4-[3- methyl -6-( trifluoromethyl ) pyridin -2- yl ] phenyl }-1 H -Pyrazolo [3,4- b ] pyridin -5- yl )-6,7,8,9 - tetrahydro -5 H -benzo [7] annen -7- yl ] -3- oxa- 6- Azabicyclo [3.1.1] heptane

The title compound was prepared in an analogous manner to Example 2 from appropriate starting materials. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 13.94 (s, 1H), 8.85 (d, J = 2.1 Hz, 1H), 8.72 (d, J = 2.0 Hz, 1H), 8.25 – 8.21 (m, 2H), 8.06 – 8.01 (m, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.77 – 7.73 (m, 2H), 7.60 (d, J = 2.0 Hz, 1H), 7.53 (dd, J = 7.7, 1.9 Hz, 1H), 7.22 (d, J = 7.8 Hz, 1H), 4.12 (d, J = 10.6 Hz, 2H), 3.53 (dd, J = 18.5, 8.3 Hz, 4H), 3.19 – 3.10 (m, 1H), 3.05 – 2.86 (m, 2H), 2.77 (q, J = 15.0, 14.3 Hz, 2H), 2.49 (s, 3H), 2.38 – 2.26 (m, 1H), 1.91 – 1.77 (m , 2H), 1.65 (d, J = 7.9 Hz, 1H), 1.24 – 1.07 (m, 2H). ESI MS [M+H] ⁺ for C ₃₅ H ₃₃ F ₃ N ₅ O, calculated 596.3, found 596.3. Example 146 : (1 R )-6-[(7 S )-2-(3-{4-[3- methyl -6-( trifluoromethyl ) pyridin -2- yl ] phenyl }-1 H -pyrrolo [2,3- b ] pyridin -5- yl )-6,7,8,9 - tetrahydro -5 H -benzo [7] annen -7- yl ] -3- oxa -6 -Azabicyclo [3.1.1 ] heptane

The title compound was prepared in an analogous manner to Example 1 from appropriate starting materials. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.05 (d, J = 2.7 Hz, 1H), 8.53 (d, J = 2.1 Hz, 1H), 8.46 (d, J = 2.1 Hz, 1H), 8.03 – 7.98 (m, 2H), 7.94 – 7.88 (m, 2H), 7.77 (d, J = 7.9 Hz, 1H), 7.69 – 7.64 (m, 2H), 7.52 (s, 1H), 7.46 (d, J = 7.6 Hz, 1H), 7.19 (d, J = 7.7 Hz, 1H), 4.12 (d, J = 10.6 Hz, 2H), 3.53 (dd, J = 18.9, 8.2 Hz, 4H), 3.19 – 3.08 (m , 1H), 3.05 – 2.83 (m, 2H), 2.75 (q, J = 14.6, 13.9 Hz, 2H), 2.50 – 2.45 (m, 3H), 2.37 – 2.27 (m, 1H), 1.90 – 1.77 (m , 2H), 1.64 (d, J = 8.1 Hz, 1H), 1.29 – 1.06 (m, 2H). ESI MS [M+H] ⁺ for C ₃₆ H ₃₄ F ₃ N ₄ O, calculated 595.3, found 595.3. Example 147 : 3,6- dimethyl -2-(4-{5-[(7 S )-7- methyl -7-[(2 R )-2- methylpyrrolidin -1- yl ]- 6,7,8,9- tetrahydro -5 H -benzo [7] annen -2- yl ]-1 H -pyrrolo [2,3- b ] pyridin -3- yl } phenyl ) pyridine

The title compound was prepared in an analogous manner to Example 18 from appropriate starting materials. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.00 (d, J = 2.6 Hz, 1H), 8.51 (d, J = 2.0 Hz, 1H), 8.41 (d, J = 2.1 Hz, 1H), 7.95 (d, J = 2.6 Hz, 1H), 7.86 – 7.81 (m, 2H), 7.58 (dd, J = 7.9, 6.0 Hz, 3H), 7.47 (s, 1H), 7.42 (d, J = 8.1 Hz, 1H), 7.16 (d, J = 7.7 Hz, 1H), 7.12 (d, J = 7.8 Hz, 1H), 3.24 – 3.08 (m, 3H), 2.79 (t, J = 7.4 Hz, 1H), 2.68 – 2.52 (m, 3H), 2.45 (s, 3H), 2.32 (s, 3H), 1.90 – 1.59 (m, 5H), 1.43 – 1.24 (m, 3H), 1.00 (d, J = 6.3 Hz, 3H) , 0.90 (d, J = 5.9 Hz, 3H). ESI MS [M+H] ⁺ for C ₃₇ H ₄₁ N ₄ , calculated 541.3, found 541.3. Example 148 : 3,6- dimethyl -2-(4-{5-[(7 S )-7-( pyrrolidin -1- yl )-6,7,8,9- tetrahydro - 5H - Benzo [7] annen -2- yl ]-1 H -pyrrolo [2,3- b ] pyridin -3- yl } phenyl ) pyridine

The title compound was prepared in an analogous manner to Example 1 from appropriate starting materials. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.01 (s, 1H), 8.52 (d, J = 2.1 Hz, 1H), 8.43 (d, J = 2.1 Hz, 1H), 7.96 (d, J = 2.6 Hz, 1H), 7.89 – 7.82 (m, 2H), 7.59 (dd, J = 7.9, 5.9 Hz, 3H), 7.51 (s, 1H), 7.44 (s, 1H), 7.19 (d, J = 7.6 Hz, 1H), 7.12 (d, J = 7.8 Hz, 1H), 3.18 – 2.79 (m, 5H), 2.73 – 2.49 (m, 4H), 2.45 (s, 3H), 2.32 (s, 3H), 1.99 – 1.43 (m, 5H), 1.34 – 1.11 (m, 3H). ESI MS [M+H] ⁺ for C ₃₅ H ₃₇ N ₄ , calculated 513.3, found 513.3. Example 149 : 6-[( 7S )-2-(3-{4-[3-( oxan -4- yl ) pyridin -2- yl ] phenyl } -1H - pyrazolo [ 3,4- b ] pyridin -5- yl )-6,7,8,9 - tetrahydro -5 H -benzo [7] annen -7- yl ]-3- oxa -6- azabicyclo [3.1.1] Heptane

The title compound (trifluoroacetate salt) was prepared in an analogous manner to Example 5 from appropriate starting materials. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.88 – 9.76 (m, 1H), 8.88 (t, J = 2.0 Hz, 1H), 8.74 (d, J = 2.0 Hz, 1H), 8.52 (d, J = 4.7 Hz, 1H), 8.25 – 8.19 (m, 2H), 8.03 – 7.96 (m, 2H), 7.73 – 7.58 (m, 4H), 7.49 – 7.42 (m, 1H), 7.30 (t, J = 8.7 Hz, 1H), 4.60 (d, J = 6.4 Hz, 1H), 4.51 (s, 2H), 4.38 (d, J = 13.0 Hz, 1H), 4.16 (q, J = 12.2 Hz, 2H), 4.00 (d, J = 13.0 Hz, 2H), 3.90 – 3.83 (m, 2H), 3.23 (t, J = 11.7 Hz, 2H), 3.07 – 2.88 (m, 2H), 2.86 – 2.67 (m, 2H), 2.31 – 2.28 (m, 1H), 2.20 – 1.99 (m, 3H), 1.84 – 1.69 (m, 2H), 1.66 – 1.56 (m, 2H), 1.26 – 1.02 (m, 2H). ESI MS [M+H] ⁺ for C ₃₈ H ₄₀ N ₅ O ₂ , calculated 598.3, found 598.3. Example 150 : 6-[(7 S )-2-[3-(4-{2 H ,3 H ,4 H -pyrido [4,3- b ][1,4] oxazin -5- yl } Phenyl ) -1H - pyrazolo [3,4- b ] pyridin -5- yl ]-6,7,8,9- tetrahydro - 5H - benzo [7] annen -7- yl ] -3- oxa -6- azabicyclo [3.1.1] heptane

The title compound was prepared in an analogous manner to Example 2 from appropriate starting materials. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 13.89 (s, 1H), 8.84 (d, J = 2.0 Hz, 1H), 8.71 – 8.66 (m, 1H), 8.17 (d, J = 8.3 Hz, 2H), 7.83 (d, J = 8.3 Hz, 2H), 7.79 (d, J = 5.2 Hz, 1H), 7.58 (s, 1H), 7.52 (d, J = 7.7 Hz, 1H), 7.23 (d, J = 7.8 Hz, 1H), 6.69 (dd, J = 5.3, 0.6 Hz, 1H), 5.53 (s, 1H), 4.24 (t, J = 4.3 Hz, 2H), 4.13 (d, J = 10.8 Hz, 2H), 3.53 (dd, J = 18.7, 8.2 Hz, 4H), 3.29 – 3.24 (m, 2H), 3.19 – 3.10 (m, 1H), 3.05 – 2.86 (m, 2H), 2.85 – 2.70 (m, 2H), 2.37 – 2.28 (m, 1H), 1.90 – 1.74 (m, 2H), 1.69 – 1.62 (m, 1H), 1.27 – 1.08 (m, 2H). ESI MS [M+H] ⁺ for C ₃₅ H ₃₅ N ₆ O ₂ , calculated 571.3, found 571.3. Example 151 : 6-[( 7S )-2-[3-(4-{4- methyl - 2H , 3H , 4H - pyrido [4,3- b ][1,4] oxazine -5- yl } phenyl )-1 H -pyrazolo [3,4- b ] pyridin -5- yl ]-6,7,8,9 - tetrahydro -5 H -benzo [7] annene -7- yl ]-3- oxa -6- azabicyclo [3.1.1] heptane

The title compound was prepared in an analogous manner to Example 2 from appropriate starting materials. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 13.89 (s, 1H), 8.84 (d, J = 2.0 Hz, 1H), 8.71 (d, J = 2.0 Hz, 1H), 8.21 – 8.13 (m, 2H), 8.09 – 7.99 (m, 3H), 7.60 (s, 1H), 7.57 – 7.50 (m, 1H), 7.23 (d, J = 7.8 Hz, 1H), 6.80 (d, J = 5.3 Hz, 1H ), 4.22 – 4.17 (m, 2H), 4.13 (d, J = 10.6 Hz, 2H), 3.60 – 3.47 (m, 4H), 3.22 – 3.11 (m, 3H), 3.06 – 2.85 (m, 2H), 2.84 – 2.68 (m, 2H), 2.39 (s, 3H), 2.36 – 2.25 (m, 1H), 1.92 – 1.77 (m, 2H), 1.65 (d, J = 7.8 Hz, 1H), 1.27 – 1.06 ( m, 2H). ESI MS [M+H] ⁺ for C ₃₆ H ₃₇ N ₆ O ₂ , calculated 585.3, found 585.3. Example 152 : 6-[( 7S )-2-{3-[4-(3,4- dimethoxypyridin -2- yl ) phenyl ] -1H - pyrazolo [3,4- b ] pyridin -5- yl }-6,7,8,9 - tetrahydro - 5H - benzo [7] annen -7- yl ]-3- oxa -6- azabicyclo [3.1.1] Heptane

The title compound was prepared in an analogous manner to Example 2 from appropriate starting materials. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 13.90 (s, 1H), 8.84 (d, J = 2.1 Hz, 1H), 8.71 (d, J = 2.1 Hz, 1H), 8.31 (d, J = 5.4 Hz, 1H), 8.20 – 8.15 (m, 2H), 8.06 – 7.97 (m, 2H), 7.60 (d, J = 2.0 Hz, 1H), 7.53 (dd, J = 7.8, 2.0 Hz, 1H), 7.23 (d, J = 7.8 Hz, 1H), 7.12 (d, J = 5.5 Hz, 1H), 4.13 (d, J = 10.7 Hz, 2H), 3.91 (s, 3H), 3.66 (s, 3H), 3.53 (dd, J = 18.2, 8.3 Hz, 4H), 3.19 – 3.07 (m, 1H), 3.04 – 2.86 (m, 2H), 2.77 (q, J = 14.2 Hz, 2H), 2.37 – 2.28 (m, 1H), 1.91 – 1.76 (m, 2H), 1.65 (d, J = 7.8 Hz, 1H), 1.27 – 1.03 (m, 2H). ESI MS [M+H] ⁺ for C ₃₅ H ₃₆ N ₅ O ₃ , calculated 574.3, found 574.3. Example 153 : 6-[( 7S )-2-{3-[2- fluoro -4-(3- methylpyridin- 2- yl ) phenyl ] -1H - pyrrolo [2,3- b ] Pyridin -5- yl }-6,7,8,9 - tetrahydro - 5H - benzo [7] annen -7- yl ]-3- oxa -6- azabicyclo [3.1.1] heptan alkyl

The title compound was prepared in an analogous manner to Example 1 from appropriate starting materials. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.15 (d, J = 2.6 Hz, 1H), 8.54 (d, J = 2.1 Hz, 1H), 8.49 (ddd, J = 4.7, 1.7, 0.7 Hz, 1H), 8.27 (s, 1H), 7.90 – 7.85 (m, 2H), 7.73 (ddd, J = 7.6, 1.7, 0.8 Hz, 1H), 7.54 – 7.46 (m, 3H), 7.45 – 7.39 (m, 1H), 7.30 (dd, J = 7.7, 4.7 Hz, 1H), 7.19 (d, J = 7.8 Hz, 1H), 4.17 – 4.07 (m, 2H), 3.61 – 3.43 (m, 4H), 3.17 – 3.07 (m, 1H), 3.02 – 2.82 (m, 2H), 2.81 – 2.67 (m, 2H), 2.40 (s, 3H), 2.37 – 2.28 (m, 1H), 1.90 – 1.74 (m, 2H), 1.64 (d, J = 8.0 Hz, 1H), 1.27 – 1.02 (m, 2H). ESI MS [M+H] ⁺ for C ₃₅ H ₃₄ FN ₄ O, calculated 545.3, found 545.3. Example 154 : 6-[( 7S )-2-{3-[4-( pyridin -2- yl ) phenyl ] -2H - pyrazolo [3,4- b ] pyridin -5- yl }- 6,7,8,9- tetrahydro - 5H - benzo [7] annen -7- yl ]-3- oxa -6- azabicyclo [3.1.1] heptane

The title compound was prepared in an analogous manner to Example 2 from appropriate starting materials. ¹ H NMR (400 MHz, chloroform- d ) δ 12.16 (s, 1H), 8.84 (d, J = 2.0 Hz, 1H), 8.75 – 8.68 (m, 1H), 8.51 (d, J = 2.0 Hz, 1H ), 8.21 – 8.08 (m, 4H), 7.84 – 7.72 (m, 2H), 7.38 (d, J = 6.5 Hz, 2H), 7.29 – 7.20 (m, 2H), 4.30 (d, J = 10.7 Hz, 2H), 3.73 (d, J = 10.7 Hz, 2H), 3.65 (d, J = 6.1 Hz, 2H), 3.31 – 3.21 (m, 1H), 3.05 – 2.92 (m, 2H), 2.85 (q, J = 13.5, 12.8 Hz, 2H), 2.57 (q, J = 6.7 Hz, 1H), 2.00 – 1.89 (m, 2H), 1.84 (d, J = 8.3 Hz, 1H), 1.36 (q, J = 11.5 Hz , 2H). ESI MS [M+H] ⁺ for C ₃₃ H ₃₂ N ₅ O, calculated 514.3, found 514.3. Example 155 : 6-[( 7S )-2-{3-[4-( pyridin -2- yl ) phenyl ] -1H - pyrrolo [2,3- b ] pyridin -5- yl }-6 ,7,8,9- tetrahydro - 5H - benzo [7] annen -7- yl ]-3- oxa -6- azabicyclo [3.1.1] heptane

The title compound was prepared in an analogous manner to Example 1 from appropriate starting materials. ¹ H NMR (400 MHz, chloroform- d ) δ 10.09 (s, 1H), 8.74 – 8.67 (m, 1H), 8.60 (d, J = 2.1 Hz, 1H), 8.42 (d, J = 2.0 Hz, 1H ), 8.14 – 8.06 (m, 2H), 7.83 – 7.71 (m, 4H), 7.62 (d, J = 2.4 Hz, 1H), 7.42 – 7.35 (m, 2H), 7.27 – 7.17 (m, 2H), 4.29 (d, J = 10.7 Hz, 2H), 3.71 (d, J = 10.7 Hz, 2H), 3.63 (d, J = 6.1 Hz, 2H), 3.29 – 3.19 (m, 1H), 2.97 (td, J = 15.0, 7.9 Hz, 2H), 2.84 (q, J = 13.1, 12.6 Hz, 2H), 2.54 (q, J = 6.7 Hz, 1H), 1.98 – 1.90 (m, 2H), 1.83 (d, J = 8.2 Hz, 1H), 1.40 – 1.27 (m, 2H). ESI MS [M+H] ⁺ for C ₃₄ H ₃₃ N ₄ O, calculated 513.3, found 513.3. Example 156 : 2-(4-{5-[(7 S )-7- methyl- 7-[(2 R )-2- methylpyrrolidin- 1- yl ]-6,7,8,9- Tetrahydro -5 H -benzo [7] annen -2- yl ]-1 H -pyrrolo [2,3- b ] pyridin -3- yl } phenyl ) pyridine

The title compound was prepared in an analogous manner to Example 1 from appropriate starting materials. ¹ H NMR (400 MHz, chloroform- d ) δ 9.57 (s, 1H), 8.74 – 8.66 (m, 1H), 8.60 (d, J = 2.0 Hz, 1H), 8.41 (d, J = 2.0 Hz, 1H ), 8.14 – 8.06 (m, 2H), 7.82 – 7.71 (m, 4H), 7.61 (d, J = 2.3 Hz, 1H), 7.37 (s, 2H), 7.26 – 7.17 (m, 2H), 3.84 ( s, 1H), 3.29 (m, 3H), 2.89 (s, 2H), 2.62 (m, 3H), 2.02 – 1.65 (m, 6H), 1.46 (s, 2H), 1.02 (m, 4H). ESI MS [M+H] ⁺ for C ₃₅ H ₃₇ N ₄ , calculated 513.3, found 513.3. Example 157 : 6-[( 7S )-2-{3-[4-( pyridin -3- yl ) phenyl ] -2H - pyrazolo [3,4- b ] pyridin -5- yl }- 6,7,8,9- tetrahydro - 5H - benzo [7] annen -7- yl ]-3- oxa -6- azabicyclo [3.1.1] heptane

The title compound was prepared in an analogous manner to Example 2 from appropriate starting materials. ¹ H NMR (400 MHz, chloroform- d ) δ 11.05 (s, 1H), 8.93 (s, 1H), 8.82 (d, J = 2.0 Hz, 1H), 8.65 – 8.59 (m, 1H), 8.52 – 8.47 (m, 1H), 8.18 – 8.07 (m, 2H), 7.95 (ddd, J = 7.9, 2.4, 1.6 Hz, 1H), 7.81 – 7.73 (m, 2H), 7.44 – 7.30 (m, 3H), 7.22 (s, 1H), 4.38 (d, J = 12.0 Hz, 2H), 4.01 (bs, 1H), 3.47 (bs, 1H), 2.97 (m, 2H), 2.85 (m, 3H), 2.00 (bs, 2H), 1.62 (m, 3H), 1.24 (bs, 2H), 0.90 – 0.81 (m, 1H). ESI MS [M+H] ⁺ for C ₃₃ H ₃₂ N ₅ O, calculated 514.3, found 514.3. Example 158 : 6-[( 7S )-2-{3-[4-( pyridin -3- yl ) phenyl ] -1H - pyrrolo [2,3- b ] pyridin -5- yl }-6 ,7,8,9- tetrahydro - 5H - benzo [7] annen -7- yl ]-3- oxa -6- azabicyclo [3.1.1] heptane

The title compound was prepared in an analogous manner to Example 1 from appropriate starting materials. ¹ H NMR (400 MHz, chloroform- d ) δ 10.81 (s, 1H), 8.91 (dd, J = 2.3, 0.9 Hz, 1H), 8.64 – 8.56 (m, 2H), 8.41 (d, J = 2.0 Hz , 1H), 7.92 (ddd, J = 7.9, 2.4, 1.6 Hz, 1H), 7.85 – 7.75 (m, 2H), 7.75 – 7.60 (m, 3H), 7.41 – 7.36 (m, 3H), 7.21 (d , J = 8.3 Hz, 1H), 4.29 (d, J = 10.6 Hz, 2H), 3.72 (d, J = 10.6 Hz, 2H), 3.63 (d, J = 6.1 Hz, 2H), 3.47 (d, J = 4.9 Hz, 1H), 3.24 (d, J = 9.5 Hz, 1H), 3.04 – 2.91 (m, 2H), 2.84 (q, J = 12.8, 12.4 Hz, 2H), 2.55 (q, J = 6.8 Hz , 1H), 1.93 (t, J = 10.8 Hz, 2H), 1.83 (d, J = 8.2 Hz, 1H), 1.32 (s, 1H). ESI MS [M+H] ⁺ for C ₃₄ H ₃₃ N ₄ O, calculated 513.3, found 513.3. Example 159 : 6-[( 7S )-2-{3-[3- methyl -4-( pyridin -2- yl ) phenyl ] -2H - pyrazolo [3,4- b ] pyridine- 5- yl }-6,7,8,9 - tetrahydro - 5H - benzo [7] annen -7- yl ]-3- oxa -6- azabicyclo [3.1.1] heptane

The title compound was prepared in an analogous manner to Example 2 from appropriate starting materials. ¹ H NMR (400 MHz, chloroform- d ) δ 12.50 (s, 1H), 8.84 (d, J = 2.1 Hz, 1H), 8.72 (ddd, J = 4.8, 1.9, 0.9 Hz, 1H), 8.49 (d , J = 2.0 Hz, 1H), 7.95 – 7.85 (m, 2H), 7.76 (td, J = 7.7, 1.8 Hz, 1H), 7.57 (d, J = 7.9 Hz, 1H), 7.46 (dt, J = 7.8, 1.1 Hz, 1H), 7.37 (d, J = 6.3 Hz, 2H), 7.30 – 7.19 (m, 2H), 4.30 (d, J = 10.7 Hz, 2H), 3.73 (d, J = 10.7 Hz, 2H), 3.65 (d, J = 6.1 Hz, 2H), 3.31 – 3.21 (m, 1H), 3.05 – 2.92 (m, 2H), 2.85 (q, J = 13.5, 12.8 Hz, 2H), 2.57 (q , J = 6.7 Hz, 1H), 2.48 (s, 3H), 2.00 – 1.89 (m, 2H), 1.84 (d, J = 8.3 Hz, 1H), 1.36 (q, J = 11.5 Hz, 2H). ESI MS [M+H] ⁺ for C ₃₄ H ₃₄ N ₅ O, calculated 528.3, found 528.3. Example 160 : 6-[( 7S )-2-{3-[3- methoxy -4-( pyridin -2- yl ) phenyl ] -2H - pyrazolo [3,4- b ] pyridine -5- yl }-6,7,8,9 - tetrahydro - 5H - benzo [7] annen -7- yl ]-3- oxa -6- azabicyclo [3.1.1] heptane

The title compound was prepared in an analogous manner to Example 2 from appropriate starting materials. ¹ H NMR (400 MHz, chloroform- d ) δ 13.18 (s, 1H), 8.84 (d, J = 2.0 Hz, 1H), 8.72 (ddd, J = 4.8, 1.9, 1.0 Hz, 1H), 8.48 (d , J = 2.1 Hz, 1H), 8.00 – 7.93 (m, 1H), 7.90 (dt, J = 8.0, 1.1 Hz, 1H), 7.75 – 7.64 (m, 3H), 7.40 – 7.32 (m, 2H), 7.27 – 7.17 (m, 2H), 4.30 (d, J = 10.7 Hz, 2H), 3.69 (s, 3H), 3.73 (d, J = 10.7 Hz, 2H), 3.65 (d, J = 6.1 Hz, 2H ), 3.31 – 3.21 (m, 1H), 3.05 – 2.92 (m, 2H), 2.85 (q, J = 13.5, 12.8 Hz, 2H), 2.57 (q, J = 6.7 Hz, 1H), 2.00 – 1.89 ( m, 2H), 1.84 (d, J = 8.3 Hz, 1H), 1.36 (q, J = 11.5 Hz, 2H). ESI MS [M+H] ⁺ for C ₃₄ H ₃₄ N ₅ O ₂ , calculated 544.3, found 544.3. Example 161 : 6-[ ( 7S )-2-{3-[3- methoxy -4-( pyridin -2- yl ) phenyl ] -1H - pyrrolo [2,3- b ] pyridine- 5- yl }-6,7,8,9 - tetrahydro - 5H - benzo [7] annen -7- yl ]-3- oxa -6- azabicyclo [3.1.1] heptane

The title compound was prepared in an analogous manner to Example 1 from appropriate starting materials. ¹ H NMR (400 MHz, chloroform- d ) δ 11.58 – 11.52 (m, 1H), 8.72 (ddd, J = 4.9, 1.9, 1.0 Hz, 1H), 8.62 (d, J = 2.1 Hz, 1H), 8.40 (d, J = 2.1 Hz, 1H), 7.93 – 7.84 (m, 2H), 7.70 (ddd, J = 8.0, 7.5, 1.9 Hz, 1H), 7.60 (d, J = 2.1 Hz, 1H), 7.43 – 7.34 (m, 3H), 7.27 – 7.15 (m, 3H), 4.29 (d, J = 10.7 Hz, 2H), 3.89 (s, 3H), 3.72 (d, J = 10.8 Hz, 2H), 3.64 (d , J = 6.1 Hz, 2H), 3.25 (dd, J = 11.3, 7.8 Hz, 1H), 2.96 (dt, J = 17.0, 8.7 Hz, 2H), 2.89 – 2.76 (m, 2H), 2.56 (q, J = 6.7 Hz, 1H), 1.93 (t, J = 10.6 Hz, 2H), 1.83 (d, J = 8.3 Hz, 1H), 1.33 (d, J = 9.7 Hz, 2H). ESI MS [M+H] ⁺ for C ₃₅ H ₃₅ N ₄ O ₂ , calculated 543.3, found 543.3. Example 162 : 6-[( 7S )-2-{3-[4-(6- methoxypyridin -2- yl ) phenyl ] -2H - pyrazolo [3,4- b ] pyridine- 5- yl }-6,7,8,9 - tetrahydro - 5H - benzo [7] annen -7- yl ]-3- oxa -6- azabicyclo [3.1.1] heptane

Material. ¹ H NMR (400 MHz, chloroform- d ) δ 10.86 (s, 1H), 8.81 (d, J = 2.0 Hz, 1H), 8.50 (dd, J = 7.4, 2.0 Hz, 1H), 8.29 – 8.19 (m , 2H), 8.14 – 8.04 (m, 2H), 7.65 (dd, J = 8.2, 7.4 Hz, 1H), 7.44 – 7.35 (m, 3H), 7.23 (d, J = 7.6 Hz, 1H), 6.71 ( dd, J = 8.2, 0.6 Hz, 1H), 4.36 (d, J = 11.7 Hz, 2H), 4.06 (s, 3H), 3.94 (m, 2H), 3.47 (d, J = 5.5 Hz, 2H), 3.06 – 2.93 (m, 3H), 2.84 (q, J = 11.7 Hz, 3H), 1.99 (m, 2H), 1.24 (m, 3H). ESI MS [M+H] ⁺ for C ₃₄ H ₃₄ N ₅ O ₂ , calculated 544.3, found 544.3. Example 163 : 3- methyl -2-(4-{5-[(7 S )-7- methyl -7-[(2 R )-2- methylpyrrolidin -1- yl ]-6,7 ,8,9- tetrahydro -5 H -benzo [7] annen -2- yl ]-2 H -pyrazolo [3,4- b ] pyridin -3- yl } phenyl ) pyridine

The title compound was prepared in an analogous manner to Example 2 from appropriate starting materials. ¹ H NMR (400 MHz, chloroform- d ) δ 12.68 (s, 1H), 8.91 (d, J = 2.0 Hz, 1H), 8.56 (ddd, J = 4.8, 1.6, 0.7 Hz, 1H), 8.52 (d , J = 2.1 Hz, 1H), 8.14 – 8.06 (m, 2H), 7.76 – 7.68 (m, 2H), 7.61 (ddt, J = 7.7, 1.7, 0.7 Hz, 1H), 7.37 (dq, J = 4.8 , 2.0 Hz, 2H), 7.25 – 7.16 (m, 2H), 3.23 (bs, 2H), 2.91 (bs, 1H), 2.73 – 2.46 (m, 3H), 2.43 (s, 3H), 1.90 (m, 4H), 1.77 – 1.61 (m, 3H), 1.54 (bs, 3H), 1.03 (m, 5H). ESI MS [M+H] ⁺ for C ₃₅ H ₃₈ N ₅ , calculated 528.3, found 528.3. Example 164 : 6-[( 7S )-2-{3-[4-(3- methoxypyridin -2- yl ) phenyl ] -1H - pyrrolo [2,3- b ] pyridine -5 -yl } -6,7,8,9 - tetrahydro - 5H - benzo [7] annen -7- yl ]-3- oxa -6- azabicyclo [3.1.1] heptane

The title compound was prepared in an analogous manner to Example 1 from appropriate starting materials. ¹ H NMR (400 MHz, chloroform- d ) δ 10.08 (d, J = 2.4 Hz, 1H), 8.60 (d, J = 2.0 Hz, 1H), 8.44 (d, J = 2.0 Hz, 1H), 8.33 ( dd, J = 4.6, 1.4 Hz, 1H), 8.07 – 7.99 (m, 2H), 7.79 – 7.71 (m, 2H), 7.59 (d, J = 2.4 Hz, 1H), 7.39 (dq, J = 3.8, 2.0 Hz, 2H), 7.30 (dd, J = 8.4, 1.4 Hz, 1H), 7.27 – 7.17 (m, 2H), 4.29 (d, J = 10.7 Hz, 2H), 3.90 (s, 3H), 3.75 – 3.67 (m, 2H), 3.63 (d, J = 6.1 Hz, 2H), 3.29 – 3.19 (m, 1H), 2.98 (m, 2H), 2.83 (q, J = 13.7, 13.3 Hz, 2H), 2.62 – 2.49 (m, 1H), 1.92 (d, J = 8.3 Hz, 2H), 1.83 (d, J = 8.2 Hz, 1H), 1.32 (m, 2H). ESI MS [M+H] ⁺ for C ₃₅ H ₃₅ N ₄ O ₂ , calculated 543.3, found 543.3. Example 165 : N,N - dimethyl -2-(4-{5-[(7 S )-7-{3- oxa -6- azabicyclo [3.1.1] hept -6- yl }- 6,7,8,9- tetrahydro -5 H -benzo [7] annen - 2- yl ]-1 H -pyrrolo [2,3- b ] pyridin -3- yl } phenyl ) pyridine- 3- methamide

The title compound was prepared in an analogous manner to Example 1 from appropriate starting materials. ¹ H NMR (400 MHz, chloroform- d ) δ 10.90 (s, 1H), 8.74 (dd, J = 4.8, 1.8 Hz, 1H), 8.58 (s, 1H), 8.41 (d, J = 1.6 Hz, 1H ), 7.87 – 7.72 (m, 4H), 7.64 (s, 1H), 7.42 – 7.34 (m, 2H), 7.31 (dd, J = 7.7, 4.8 Hz, 1H), 7.25 – 7.14 (m, 2H), 4.34 (d, J = 11.4 Hz, 2H), 3.97 (bs, 2H), 3.86 (d, J = 11.4 Hz, 2H), 3.45 (s, 3H), 3.33 (d, J = 10.7 Hz, 1H), 2.96 (s, 3H), 2.93 – 2.75 (m, 5H), 2.04 – 1.87 (m, 3H), 1.58 – 1.39 (m, 2H). ESI MS [M+H] ⁺ for C ₃₇ H ₃₈ N ₅ O ₂ , calculated 584.3, found 584.3. Example 166 : 6-[( 7S )-2-{3-[4-(3- methoxypyridin -2- yl ) phenyl ] -1H - pyrazolo [3,4- b ] pyridine- 5- yl }-6,7,8,9 - tetrahydro - 5H - benzo [7] annen -7- yl ]-3- oxa -6- azabicyclo [3.1.1] heptane

The title compound was prepared in an analogous manner to Example 2 from appropriate starting materials. ¹ H NMR (400 MHz, chloroform- d ) δ 12.33 (s, 1H), 8.85 (d, J = 2.1 Hz, 1H), 8.52 (d, J = 2.0 Hz, 1H), 8.33 (dd, J = 4.6 , 1.4 Hz, 1H), 8.14 – 8.04 (m, 4H), 7.41 – 7.35 (m, 2H), 7.31 (dd, J = 8.4, 1.4 Hz, 1H), 7.28 – 7.19 (m, 2H), 4.30 ( d, J = 10.7 Hz, 2H), 3.89 (s, 3H), 3.73 (d, J = 10.7 Hz, 2H), 3.65 (d, J = 6.1 Hz, 2H), 3.25 (t, J = 9.9 Hz, 1H), 3.03 – 2.78 (m, 4H), 2.56 (q, J = 7.0 Hz, 1H), 1.98 – 1.91 (m, 2H), 1.84 (d, J = 8.3 Hz, 1H), 1.37 (bs, 2H ). ESI MS [M+H] ⁺ for C ₃₄ H ₃₄ N ₅ O ₂ , calculated 544.3, found 544.3. Example 167 : N,N - dimethyl -2-(4-{5-[(7 S )-7-{3- oxa -6- azabicyclo [3.1.1] hept -6- yl }- 6,7,8,9- tetrahydro -5 H -benzo [7] annen -2- yl ]-1 H -pyrazolo [3,4- b ] pyridin - 3- yl } phenyl ) pyridine -3- methamide

The title compound was prepared in an analogous manner to Example 2 from appropriate starting materials. ¹ H NMR (400 MHz, chloroform- d ) δ 12.07 (s, 1H), 8.85 (d, J = 2.0 Hz, 1H), 8.76 (dd, J = 4.8, 1.7 Hz, 1H), 8.50 (d, J = 2.0 Hz, 1H), 8.15 – 8.07 (m, 2H), 7.96 – 7.87 (m, 2H), 7.78 (dd, J = 7.7, 1.7 Hz, 1H), 7.42 – 7.31 (m, 3H), 7.24 ( d, J = 8.3 Hz, 1H), 4.30 (d, J = 10.7 Hz, 2H), 3.73 (d, J = 10.7 Hz, 2H), 3.65 (d, J = 6.1 Hz, 2H), 3.31 – 3.21 ( m, 1H), 2.95 (m, 5H), 2.86 (m, 2H), 2.56 (q, J = 6.8 Hz, 1H), 2.47 (s, 3H), 1.94 (bs, 2H), 1.84 (d, J = 8.3 Hz, 1H), 1.35 (m, 2H). ESI MS [M+H] ⁺ for C ₃₆ H ₃₇ N ₆ O ₂ , calculated 585.3, found 585.3. Example 168 : 6-[( 7S )-2-{3-[1-( pyridin -2- yl ) -1H - pyrazol -4- yl ] -1H - pyrazolo [3,4- b ] pyridin -5- yl }-6,7,8,9 - tetrahydro - 5H - benzo [7] annen -7- yl ]-3- oxa -6- azabicyclo [3.1.1] Heptane

The title compound was prepared in an analogous manner to Example 2 from appropriate starting materials. ¹ H NMR (400 MHz, chloroform- d ) δ 13.01 (s, 1H), 9.11 (d, J = 0.9 Hz, 1H), 8.81 (d, J = 2.0 Hz, 1H), 8.48 – 8.36 (m, 2H ), 8.33 (d, J = 0.8 Hz, 1H), 8.03 (dt, J = 8.2, 1.0 Hz, 1H), 7.82 (ddd, J = 8.3, 7.4, 1.8 Hz, 1H), 7.36 (dq, J = 3.2, 2.0 Hz, 2H), 7.25 – 7.16 (m, 2H), 4.31 (d, J = 10.7 Hz, 2H), 3.74 (d, J = 10.7 Hz, 2H), 3.68 (d, J = 6.1 Hz, 2H), 3.32 – 3.22 (m, 1H), 3.04 – 2.90 (m, 2H), 2.90 – 2.77 (m, 2H), 2.65 – 2.55 (m, 1H), 1.95 (t, J = 10.1 Hz, 2H) , 1.85 (d, J = 8.3 Hz, 1H), 1.39 (q, J = 11.3 Hz, 2H). ESI MS [M+H] ⁺ for C ₃₀ H ₃₀ N ₇ O, calculated 504.2, found 504.2. Example 169 : 6-[( 7S )-2-{3-[4-(4- methyl - 4H -1,2,4- triazol -3- yl ) phenyl ] -1H - pyrazole And [3,4- b ] pyridin -5- yl }-6,7,8,9 - tetrahydro -5 H -benzo [7] annen -7- yl ]-3- oxa -6- nitrogen Heterobicyclo [3.1.1] heptane

The title compound was prepared in an analogous manner to Example 2 from appropriate starting materials. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 13.98 (s, 1H), 8.85 (d, J = 2.1 Hz, 1H), 8.72 (d, J = 2.1 Hz, 1H), 8.58 (s, 1H) , 8.30 – 8.22 (m, 2H), 7.93 – 7.85 (m, 2H), 7.59 (d, J = 2.0 Hz, 1H), 7.52 (dd, J = 7.7, 2.0 Hz, 1H), 7.22 (d, J = 7.8 Hz, 1H), 4.12 (d, J = 10.6 Hz, 2H), 3.79 (s, 3H), 3.55 (d, J = 10.6 Hz, 2H), 3.50 (d, J = 6.1 Hz, 2H), 3.14 (s, 1H), 2.95 (m, 2H), 2.76 (m, 2H), 2.32 (q, J = 6.8 Hz, 1H), 1.83 (bs, 2H), 1.64 (d, J = 7.9 Hz, 1H ), 1.16 (bs, 2H). ESI MS [M+H] ⁺ for C ₃₁ H ₃₂ N ₇ O, calculated 518.3, found 518.3. Example 170 : N,N - dimethyl -2-(5-{5-[(7 S )-7-{3- oxa -6- azabicyclo [3.1.1] hept -6- yl }- 6,7,8,9- tetrahydro -5 H -benzo [7] annuen -2- yl ]-1 H -pyrrolo [2,3- b ] pyridin - 3- yl } pyridin -2- yl ) benzamide

The title compound was prepared in an analogous manner to Example 1 from appropriate starting materials. ¹ H NMR (400 MHz, chloroform- d ) δ 10.82 (s, 1H), 9.00 (dd, J = 2.3, 0.9 Hz, 1H), 8.60 (d, J = 2.1 Hz, 1H), 8.35 (d, J = 2.1 Hz, 1H), 7.97 (dd, J = 8.2, 2.3 Hz, 1H), 7.80 – 7.76 (m, 1H), 7.67 (dd, J = 8.2, 0.9 Hz, 1H), 7.63 (s, 1H) , 7.52 – 7.34 (m, 5H), 7.18 (dd, J = 7.6, 2.2 Hz, 1H), 4.35 (d, J = 11.4 Hz, 2H), 3.98 (s, 2H), 3.86 (d, J = 11.4 Hz, 2H), 3.46 (d, J = 1.4 Hz, 1H), 3.36 (t, J = 10.2 Hz, 1H), 3.00 (s, 3H), 2.99 – 2.76 (m, 4H), 2.64 (s, 3H ), 1.93 (d, J = 8.9 Hz, 3H), 1.57 – 1.46 (m, 2H). ESI MS [M+H] ⁺ for C ₃₇ H ₃₈ N ₅ O ₂ , calculated 584.3, found 584.3. Example 171 : 6-[( 7S )-2-(3-{4-[3-( pyrrolidin -1- carbonyl ) pyridin -2- yl ] phenyl } -1H - pyrrolo [2,3- b ] Pyridin -5- yl )-6,7,8,9- tetrahydro - 5H - benzo [7] annen -7- yl ]-3- oxa -6- azabicyclo [3.1.1 ] Heptane

The title compound was prepared in an analogous manner to Example 1 from appropriate starting materials. ¹ H NMR (400 MHz, chloroform- d ) δ 10.91 (s, 1H), 8.74 (dd, J = 4.8, 1.8 Hz, 1H), 8.61 (d, J = 2.0 Hz, 1H), 8.41 (d, J = 2.0 Hz, 1H), 7.93 – 7.84 (m, 2H), 7.77 (td, J = 7.4, 7.0, 1.8 Hz, 3H), 7.65 (d, J = 2.2 Hz, 1H), 7.39 (d, J = 6.7 Hz, 2H), 7.31 (dd, J = 7.7, 4.8 Hz, 1H), 7.24 – 7.17 (m, 1H), 4.37 – 4.29 (m, 2H), 3.82 (d, J = 11.5 Hz, 4H), 3.49 (d, J = 24.9 Hz, 3H), 3.39 – 3.29 (m, 1H), 3.07 – 2.84 (m, 3H), 2.82 (s, 2H), 2.79 (s, 1H), 1.97 (d, J = 10.8 Hz, 2H), 1.90 (d, J = 8.6 Hz, 1H), 1.74 – 1.66 (m, 2H), 1.55 (d, J = 13.4 Hz, 4H). ESI MS [M+H] ⁺ for C ₃₉ H ₄₀ N ₅ O ₂ , calculated 610.3, found 610.3. Example 172 : 3- methyl -2-(4-{5-[(7 S )-7- methyl -7-[(2 R )-2- methylpyrrolidin -1- yl ]-6,7 ,8,9- tetrahydro -5 H -benzo [7] annen -2- yl ]-1 H -pyrrolo [2,3- b ] pyridin -3- yl } phenyl ) pyridine

Material. ¹ H NMR (400 MHz, chloroform- d ) δ 9.97 (s, 1H), 8.58 (d, J = 2.0 Hz, 1H), 8.54 (ddd, J = 4.8, 1.7, 0.7 Hz, 1H), 8.42 (d , J = 2.1 Hz, 1H), 7.79 – 7.71 (m, 2H), 7.67 – 7.54 (m, 4H), 7.40 – 7.32 (m, 2H), 7.22 – 7.14 (m, 2H), 3.23 (bs, 2H ), 2.91 (bs, 1H), 2.73 – 2.46 (m, 3H), 2.43 (s, 3H), 1.94 – 1.82 (m, 3H), 1.77 – 1.61 (m, 3H), 1.54 (bs, 4H), 1.07 – 1.00 (m, 5H). ESI MS [M+H] ⁺ for C ₃₆ H ₃₉ N ₄ , calculated 527.3, found 527.3. Example 173 : 3- methyl -2-(4-{5-[( 7S )-7-( pyrrolidin -1- yl )-6,7,8,9- tetrahydro - 5H - benzo [ 7] Annen -2- yl ]-1 H -pyrrolo [2,3- b ] pyridin -3- yl } phenyl ) pyridine

The title compound was prepared in an analogous manner to Example 1 from appropriate starting materials. ¹ H NMR (400 MHz, chloroform- d ) δ 10.37 (s, 1H), 8.58 (d, J = 2.0 Hz, 1H), 8.53 (ddd, J = 4.8, 1.7, 0.7 Hz, 1H), 8.42 (d , J = 2.1 Hz, 1H), 7.78 – 7.70 (m, 2H), 7.66 – 7.54 (m, 4H), 7.37 (d, J = 6.6 Hz, 2H), 7.23 – 7.14 (m, 2H), 3.07 – 2.93 (m, 2H), 2.80 – 2.69 (m, 2H), 2.66 – 2.60 (m, 4H), 2.57 – 2.52 (m, 1H), 2.43 (s, 3H), 2.14 (d, J = 7.2 Hz, 2H), 1.79 – 1.75 (m, 4H), 1.59 – 1.56 (m, 2H). ESI MS [M+H] ⁺ for C ₃₄ H ₃₅ N ₄ , calculated 499.3, found 499.5. Example 174 : 6-[( 7S )-2-{3-[4-(5- methylpyrimidin -4- yl ) phenyl ] -1H - pyrazolo [3,4- b ] pyridine -5 -yl } -6,7,8,9 - tetrahydro - 5H - benzo [7] annen -7- yl ]-3- oxa -6- azabicyclo [3.1.1] heptane

The title compound was prepared in an analogous manner to Example 2 from appropriate starting materials. ¹ H NMR (400 MHz, chloroform- d ) δ 13.04 – 12.99 (m, 1H), 9.15 (t, J = 0.5 Hz, 1H), 8.85 (d, J = 2.1 Hz, 1H), 8.64 (d, J = 0.8 Hz, 1H), 8.50 (d, J = 2.0 Hz, 1H), 8.17 – 8.09 (m, 2H), 7.84 – 7.76 (m, 2H), 7.38 (d, J = 6.7 Hz, 2H), 7.27 – 7.19 (m, 1H), 4.31 (d, J = 10.7 Hz, 2H), 3.74 (d, J = 10.7 Hz, 2H), 3.67 (d, J = 6.1 Hz, 2H), 3.32 – 3.22 (m, 1H), 2.96 (dd, J = 14.5, 6.9 Hz, 2H), 2.86 (q, J = 12.0 Hz, 2H), 2.64 – 2.54 (m, 1H), 2.45 (t, J = 0.7 Hz, 3H), 1.94 (d, J = 9.9 Hz, 2H), 1.85 (d, J = 8.3 Hz, 1H), 1.38 (q, J = 11.3 Hz, 2H). ESI MS [M+H] ⁺ for C ₃₃ H ₃₃ N ₆ O, calculated 529.3, found 529.3. Example 175 : 6-[( 7S )-2-{3-[4-(3- methylpyrazin -2- yl ) phenyl ] -1H - pyrazolo [3,4- b ] pyridine- 5- yl }-6,7,8,9 - tetrahydro - 5H - benzo [7] annen -7- yl ]-3- oxa -6- azabicyclo [3.1.1] heptane

The title compound was prepared in an analogous manner to Example 2 from appropriate starting materials. ¹ H NMR (400 MHz, chloroform- d ) δ 13.20 (s, 1H), 8.85 (d, J = 2.0 Hz, 1H), 8.52 – 8.49 (m, 2H), 8.46 (d, J = 2.5 Hz, 1H ), 8.16 – 8.08 (m, 2H), 7.79 – 7.71 (m, 2H), 7.37 (d, J = 6.5 Hz, 2H), 7.24 – 7.20 (m, 1H), 4.31 (d, J = 10.6 Hz, 2H), 3.74 (d, J = 10.7 Hz, 2H), 3.68 (d, J = 6.1 Hz, 2H), 3.26 (dq, J = 9.6, 5.2, 3.3 Hz, 1H), 2.97 (dt, J = 16.8 , 10.0 Hz, 2H), 2.85 (q, J = 13.1, 12.2 Hz, 2H), 2.70 (d, J = 0.6 Hz, 3H), 2.64 – 2.54 (m, 1H), 2.01 – 1.91 (m, 2H) , 1.85 (d, J = 8.3 Hz, 1H), 1.38 (q, J = 11.4 Hz, 2H). ESI MS [M+H] ⁺ for C ₃₃ H ₃₃ N ₆ O, calculated 529.3, found 529.3. Example 176 : 6-[( 7S )-2-{3-[4-(4- methylpyridazin -3- yl ) phenyl ] -1H - pyrazolo [3,4- b ] pyridine- 5- yl }-6,7,8,9 - tetrahydro - 5H - benzo [7] annen -7- yl ]-3- oxa -6- azabicyclo [3.1.1] heptane

The title compound was prepared in an analogous manner to Example 2 from appropriate starting materials. ¹ H NMR (400 MHz, chloroform- d ) δ 13.20 (s, 1H), 8.85 (d, J = 2.0 Hz, 1H), 8.52 – 8.49 (m, 2H), 8.46 (d, J = 2.5 Hz, 1H ), 8.16 – 8.08 (m, 2H), 7.79 – 7.71 (m, 2H), 7.37 (d, J = 6.5 Hz, 2H), 7.24 – 7.20 (m, 1H), 4.31 (d, J = 10.6 Hz, 2H), 3.74 (d, J = 10.7 Hz, 2H), 3.68 (d, J = 6.1 Hz, 2H), 3.26 (dq, J = 9.6, 5.2, 3.3 Hz, 1H), 2.97 (dt, J = 16.8 , 10.0 Hz, 2H), 2.85 (q, J = 13.1, 12.2 Hz, 2H), 2.70 (d, J = 0.6 Hz, 3H), 2.64 – 2.54 (m, 1H), 2.01 – 1.91 (m, 2H) , 1.85 (d, J = 8.3 Hz, 1H), 1.38 (q, J = 11.4 Hz, 2H). ESI MS [M+H] ⁺ for C ₃₃ H ₃₃ N ₆ O, calculated 529.3, found 529.3. Example 177 : 1-[2-(4-{5-[(7 S )-7-{3- oxa -6- azabicyclo [3.1.1] hept -6- yl }-6,7,8 ,9- tetrahydro -5 H -benzo [7] annen -2- yl ]-1 H -pyrazolo [3,4- b ] pyridin -3- yl } phenyl ) pyridin -3- yl ] Pyrrolidin -2- one

The title compound was prepared in an analogous manner to Example 2 from appropriate starting materials. ¹ H NMR (400 MHz, chloroform- d ) δ 11.99 (s, 1H), 8.85 (d, J = 2.0 Hz, 1H), 8.67 (dd, J = 4.7, 1.6 Hz, 1H), 8.50 (d, J = 2.1 Hz, 1H), 8.14 – 8.06 (m, 2H), 7.82 – 7.70 (m, 3H), 7.42 – 7.32 (m, 3H), 7.23 (s, 1H), 4.30 (d, J = 10.7 Hz, 2H), 3.73 (d, J = 10.7 Hz, 2H), 3.65 (d, J = 6.1 Hz, 2H), 3.35 (t, J = 7.0 Hz, 2H), 3.31 – 3.21 (m, 1H), 3.06 – 2.78 (m, 4H), 2.54 (dt, J = 26.5, 7.4 Hz, 3H), 1.99 (p, J = 9.1, 8.2 Hz, 4H), 1.84 (d, J = 8.3 Hz, 1H), 1.35 (q , J = 11.7 Hz, 2H). ESI MS [M+H] ⁺ for C ₃₇ H ₃₇ N ₆ O ₂ , calculated 597.3, found 597.3. Example 178 : 6-[( 7S )-2-{3-[4-(3- cyclopropylpyridin -2- yl ) phenyl ] -1H - pyrrolo [2,3- b ] pyridine -5 -yl } -6,7,8,9 - tetrahydro - 5H - benzo [7] annen -7- yl ]-3- oxa -6- azabicyclo [3.1.1] heptane

The title compound was prepared in an analogous manner to Example 1 from appropriate starting materials. ¹ H NMR (400 MHz, chloroform- d ) δ 10.61 (s, 1H), 8.62 (d, J = 2.0 Hz, 1H), 8.51 (dd, J = 4.7, 1.7 Hz, 1H), 8.44 (d, J = 2.0 Hz, 1H), 7.82 – 7.72 (m, 4H), 7.59 (d, J = 2.4 Hz, 1H), 7.39 (dq, J = 4.1, 2.0 Hz, 2H), 7.27 (dd, J = 7.9, 1.7 Hz, 1H), 7.23 – 7.13 (m, 2H), 4.30 (d, J = 10.7 Hz, 2H), 3.72 (d, J = 10.7 Hz, 2H), 3.64 (d, J = 6.1 Hz, 2H) , 3.23 (q, J = 9.1, 8.6 Hz, 1H), 2.98 (td, J = 19.2, 16.8, 7.9 Hz, 2H), 2.84 (q, J = 13.4 Hz, 2H), 2.55 (q, J = 6.7 Hz, 1H), 2.18 – 2.05 (m, 1H), 1.92 (bs, 2H), 1.83 (d, J = 8.2 Hz, 1H), 1.34 (q, J = 11.3, 10.7 Hz, 2H), 1.03 – 0.93 (m, 2H), 0.82 – 0.68 (m, 2H). ESI MS [M+H] ⁺ for C ₃₇ H ₃₇ N ₄ O, calculated 553.3, found 553.3. Example 179 : 6-[( 7S )-2-{3-[4-(3- cyclopropylpyridin -2- yl ) phenyl ] -1H - pyrazolo [3,4- b ] pyridine- 5- yl }-6,7,8,9 - tetrahydro - 5H - benzo [7] annen -7- yl ]-3- oxa -6- azabicyclo [3.1.1] heptane

The title compound was prepared in an analogous manner to Example 2 from appropriate starting materials. ¹ H NMR (400 MHz, chloroform- d ) δ 13.04 (s, 1H), 8.86 (d, J = 2.0 Hz, 1H), 8.54 – 8.48 (m, 2H), 8.13 – 8.05 (m, 2H), 7.89 – 7.81 (m, 2H), 7.38 (d, J = 6.2 Hz, 2H), 7.28 (ddd, J = 7.9, 1.7, 0.5 Hz, 1H), 7.26 – 7.14 (m, 2H), 4.31 (d, J = 10.7 Hz, 2H), 3.73 (d, J = 10.7 Hz, 2H), 3.67 (d, J = 6.1 Hz, 2H), 3.32 – 3.22 (m, 1H), 3.04 – 2.91 (m, 2H), 2.85 (q, J = 12.9, 12.4 Hz, 2H), 2.59 (q, J = 6.7 Hz, 1H), 2.07 (tt, J = 8.4, 5.3 Hz, 1H), 1.98 (bs, 2H), 1.85 (d, J = 8.3 Hz, 1H), 1.38 (q, J = 11.3 Hz, 2H), 1.02 – 0.90 (m, 2H), 0.80 – 0.66 (m, 2H). ESI MS [M+H] ⁺ for C ₃₆ H ₃₆ N ₅ O, calculated 554.3, found 554.3. Example 180 : 6-[( 7S )-2-(3-{4-[3-(2- methoxyethoxy ) pyridin -2- yl ] phenyl } -1H - pyrazolo [3 ,4- b ] pyridin -5- yl )-6,7,8,9 - tetrahydro -5 H -benzo [7] annen -7- yl ]-3- oxa -6- azabicyclo [ 3.1.1] Heptane

The title compound was prepared in an analogous manner to Example 2 from appropriate starting materials. ¹ H NMR (400 MHz, chloroform- d ) δ 11.93 (s, 1H), 8.85 (d, J = 2.0 Hz, 1H), 8.52 (d, J = 2.1 Hz, 1H), 8.35 (dd, J = 4.6 , 1.4 Hz, 1H), 8.21 – 8.14 (m, 2H), 8.10 – 8.04 (m, 2H), 7.41 – 7.36 (m, 2H), 7.33 (dd, J = 8.3, 1.4 Hz, 1H), 7.24 – 7.19 (m, 2H), 4.30 (d, J = 10.7 Hz, 2H), 4.22 – 4.15 (m, 2H), 3.80 – 3.69 (m, 4H), 3.65 (d, J = 6.1 Hz, 2H), 3.42 (s, 3H), 3.31 – 3.21 (m, 1H), 3.06 – 2.92 (m, 2H), 2.85 (q, J = 13.4, 12.9 Hz, 2H), 2.56 (q, J = 6.7 Hz, 1H), 1.94 (bs, 2H), 1.84 (d, J = 8.3 Hz, 1H), 1.35 (q, J = 11.6 Hz, 2H). ESI MS [M+H] ⁺ for C ₃₆ H ₃₈ N ₅ O ₃ , calculated 588.3, found 588.3. Example 181 : 6-[( 7S )-2-{3-[4-(3- ethoxypyridin -2- yl ) phenyl ] -1H - pyrazolo [3,4- b ] pyridine- 5- yl }-6,7,8,9 - tetrahydro - 5H - benzo [7] annen -7- yl ]-3- oxa -6- azabicyclo [3.1.1] heptane

The title compound was prepared in an analogous manner to Example 2 from appropriate starting materials. ¹ H NMR (400 MHz, chloroform- d ) δ 13.30 (s, 1H), 8.85 (d, J = 2.0 Hz, 1H), 8.53 (d, J = 2.0 Hz, 1H), 8.32 (dd, J = 4.6 , 1.4 Hz, 1H), 8.20 – 8.12 (m, 2H), 8.12 – 8.04 (m, 2H), 7.38 (d, J = 6.5 Hz, 2H), 7.31 – 7.16 (m, 3H), 4.31 (d, J = 10.7 Hz, 2H), 4.09 (q, J = 6.9 Hz, 2H), 3.73 (d, J = 10.7 Hz, 2H), 3.70 – 3.64 (m, 2H), 3.31 – 3.22 (m, 1H), 3.04 – 2.90 (m, 2H), 2.84 (q, J = 12.9, 12.3 Hz, 2H), 2.59 (q, J = 6.7 Hz, 1H), 2.01 – 1.90 (m, 2H), 1.85 (d, J = 8.3 Hz, 1H), 1.43 (q, J = 8.4, 7.7 Hz, 5H). ESI MS [M+H] ⁺ for C ₃₅ H ₃₆ N ₅ O ₂ , calculated 588.3, found 588.3. Example 182 : 6-[( 7S )-2-{3-[4-(3- ethylpyridin -2- yl ) phenyl ] -1H -pyrazolo [ 3,4- b ] pyridine -5 -yl } -6,7,8,9 - tetrahydro - 5H - benzo [7] annen -7- yl ]-3- oxa -6- azabicyclo [3.1.1] heptane

The title compound was prepared in an analogous manner to Example 2 from appropriate starting materials. ¹ H NMR (400 MHz, chloroform- d ) δ 13.53 (s, 1H), 8.85 (d, J = 2.0 Hz, 1H), 8.57 – 8.47 (m, 2H), 8.11 – 8.03 (m, 2H), 7.68 – 7.60 (m, 3H), 7.40 – 7.33 (m, 2H), 7.21 (td, J = 5.8, 2.7 Hz, 2H), 4.31 (d, J = 10.7 Hz, 2H), 3.74 (d, J = 10.7 Hz, 2H), 3.72 – 3.66 (m, 2H), 3.31 – 3.22 (m, 1H), 3.02 – 2.91 (m, 2H), 2.91 – 2.78 (m, 2H), 2.73 (q, J = 7.5 Hz, 2H), 2.60 (q, J = 6.7 Hz, 1H), 2.00 – 1.90 (m, 2H), 1.84 (d, J = 8.3 Hz, 1H), 1.39 (q, J = 11.5 Hz, 2H), 1.16 ( t, J = 7.5 Hz, 3H). ESI MS [M+H] ⁺ for C ₃₅ H ₃₆ N ₅ O, calculated 542.3, found 542.3. Example 183 : 6-[( 7S )-2-{3-[4-(3- ethylpyridin -2- yl ) phenyl ] -1H - pyrrolo [2,3- b ] pyridine -5- yl }-6,7,8,9- tetrahydro - 5H - benzo [7] annen -7- yl ]-3- oxa -6- azabicyclo [3.1.1] heptane

The title compound was prepared in an analogous manner to Example 1 from appropriate starting materials. ¹ H NMR (400 MHz, chloroform- d ) δ 11.43 (d, J = 2.4 Hz, 1H), 8.62 (d, J = 1.9 Hz, 1H), 8.55 (dd, J = 4.7, 1.7 Hz, 1H), 8.43 (d, J = 2.0 Hz, 1H), 7.78 – 7.70 (m, 2H), 7.67 – 7.62 (m, 1H), 7.60 – 7.54 (m, 3H), 7.39 (dq, J = 4.0, 2.0 Hz, 2H), 7.27 – 7.17 (m, 2H), 4.30 (d, J = 10.7 Hz, 2H), 3.71 (d, J = 10.7 Hz, 2H), 3.70 – 3.61 (m, 2H), 3.29 – 3.19 (m , 1H), 2.92 (m, 4H), 2.76 (q, J = 7.5 Hz, 2H), 2.60 – 2.50 (m, 1H), 1.96 (d, J = 10.8 Hz, 2H), 1.83 (d, J = 8.2 Hz, 1H), 1.34 (q, J = 11.4, 10.5 Hz, 2H), 1.19 (t, J = 7.5 Hz, 3H). ESI MS [M+H] ⁺ for C ₃₆ H ₃₇ N ₄ O, calculated 541.3, found 541.3. Example 184 : 6-[( 7S )-2-{3-[5-(3- methylpyridin -2- yl ) pyrazin -2- yl ] -1H - pyrrolo [2,3- b ] Pyridin -5- yl }-6,7,8,9 - tetrahydro - 5H - benzo [7] annen -7- yl ]-3- oxa -6- azabicyclo [3.1.1] heptan alkyl

The title compound was prepared in an analogous manner to Example 17 from appropriate starting materials. ¹ H NMR (400 MHz, chloroform- d ) δ 8.83 (dd, J = 2.4, 0.8 Hz, 1H), 8.57 (ddd, J = 4.8, 1.7, 0.7 Hz, 1H), 8.36 (d, J = 2.3 Hz , 1H), 8.09 (d, J = 2.3 Hz, 1H), 8.01 (dd, J = 8.4, 2.3 Hz, 1H), 7.88 (dd, J = 8.5, 0.8 Hz, 1H), 7.63 (ddt, J = 7.7, 1.7, 0.7 Hz, 1H), 7.32 – 7.18 (m, 2H), 7.15 (d, J = 8.2 Hz, 1H), 6.81 (bs, 1H), 3.44 – 3.12 (m, 3H), 2.89 (dd , J = 8.5, 6.7 Hz, 1H), 2.66 (td, J = 9.5, 8.7, 5.6 Hz, 1H), 2.61 – 2.50 (m, 1H), 2.44 (s, 3H), 1.96 – 1.80 (m, 3H ), 1.77 – 1.60 (m, 2H), 1.55 – 1.39 (m, 2H), 1.05 (d, J = 6.3 Hz, 2H), 0.97 (bs, 2H). ESI MS [M+H] ⁺ for C ₃₃ H ₃₃ N ₆ O, calculated 529.3, found 529.3. Example 185 : 6-[( 7S )-2-{3-[4-(3,6- dimethylpyridin -2- yl )-3- methylphenyl ] -1H - pyrazolo [3 ,4- b ] pyridin -5- yl }-6,7,8,9 - tetrahydro -5 H -benzo [7] annen -7- yl ]-3- oxa -6- azabicyclo [ 3.1.1] Heptane

The title compound was prepared in an analogous manner to Example 2 from appropriate starting materials. ¹ H NMR (400 MHz, chloroform- d ) δ 12.28 (s, 1H), 8.84 (d, J = 2.0 Hz, 1H), 8.48 (d, J = 2.0 Hz, 1H), 7.89 (d, J = 1.6 Hz, 1H), 7.85 (dd, J = 7.7, 1.7 Hz, 1H), 7.48 (d, J = 7.8 Hz, 1H), 7.37 (dq, J = 3.4, 2.0 Hz, 2H), 7.33 (d, J = 7.8 Hz, 1H), 7.23 (d, J = 3.9 Hz, 1H), 7.07 (d, J = 7.8 Hz, 1H), 4.30 (d, J = 10.7 Hz, 2H), 3.73 (d, J = 10.7 Hz, 2H), 3.65 (d, J = 6.1 Hz, 2H), 3.31 – 3.21 (m, 1H), 2.98 (td, J = 15.0, 7.8 Hz, 2H), 2.85 (q, J = 13.2 Hz, 2H ), 2.56 (s, 3H), 2.18 (s, 3H), 2.10 (s, 3H), 1.94 (bs, 2H), 1.84 (d, J = 8.3 Hz, 2H), 1.35 (q, J = 11.5 Hz , 2H). ESI MS [M+H] ⁺ for C ₃₆ H ₃₈ N ₅ O, calculated 556.3, found 556.3. Example 186 : ( 3S ) -N -[( 7S )-2-{3-[4-(3- methylpyridin -2- yl ) phenyl ] -1H - pyrrolo [2,3- b ] pyridin -5- yl }-6,7,8,9 - tetrahydro - 5H - benzo [7] annen -7- yl ] oxane -3- amine

The title compound was prepared in an analogous manner to Example 1 from appropriate starting materials. ¹ H NMR (400 MHz, chloroform- d ) δ 11.39 (s, 1H), 8.61 (d, J = 2.0 Hz, 1H), 8.56 (ddd, J = 4.8, 1.7, 0.7 Hz, 1H), 8.43 (d , J = 2.0 Hz, 1H), 7.78 – 7.70 (m, 2H), 7.65 – 7.61 (m, 2H), 7.58 (ddd, J = 8.3, 1.5, 0.7 Hz, 2H), 7.39 (dq, J = 4.7 , 2.0 Hz, 2H), 7.22 – 7.15 (m, 2H), 3.91 (ddd, J = 11.0, 4.0, 1.7 Hz, 1H), 3.79 (dt, J = 11.0, 3.8 Hz, 1H), 3.44 – 3.36 ( m, 1H), 3.17 (dd, J = 11.0, 8.4 Hz, 1H), 2.98 – 2.70 (m, 6H), 2.43 (t, J = 0.6 Hz, 3H), 2.18 – 2.01 (m, 2H), 1.99 – 1.90 (m, 1H), 1.72 – 1.57 (m, 2H), 1.41 – 1.28 (m, 3H). ESI MS [M+H] ⁺ for C ₃₅ H ₃₇ N ₄ O, calculated 529.3, found 529.3. Example 187 : (4 S )-5-[(7 S )-2-{3-[4-(3- methylpyridin -2- yl ) phenyl ]-1 H -pyrrolo [2,3- b ] pyridin -5- yl }-6,7,8,9 - tetrahydro - 5H - benzo [7] annen -7- yl ]-2- oxa -5- azabicyclo [2.2.1] Heptane

The title compound was prepared in an analogous manner to Example 1 from appropriate starting materials. ¹ H NMR (400 MHz, chloroform- d ) δ 11.14 (s, 1H), 8.61 (d, J = 2.0 Hz, 1H), 8.57 – 8.53 (m, 1H), 8.43 (d, J = 2.0 Hz, 1H ), 7.78 – 7.69 (m, 2H), 7.66 – 7.61 (m, 2H), 7.61 – 7.55 (m, 2H), 7.42 – 7.35 (m, 2H), 7.21 – 7.15 (m, 2H), 4.42 (t , J = 1.9 Hz, 1H), 4.09 (d, J = 7.8 Hz, 1H), 3.80 (s, 1H), 3.67 (dd, J = 7.9, 1.6 Hz, 1H), 3.45 (s, 2H), 3.21 – 3.14 (m, 1H), 3.06 (s, 2H), 2.83 (s, 1H), 2.72 (s, 2H), 2.53 (d, J = 9.9 Hz, 1H), 2.43 (s, 3H), 2.04 – 1.88 (m, 3H), 1.81 – 1.74 (m, 1H). ESI MS [M+H] ⁺ for C ₃₅ H ₃₅ N ₄ O, calculated 527.3, found 527.3. Example 188 : 3,5- dimethyl -2-(4-{5-[( 7S )-7- methyl -7-[( 2R )-2- methylpyrrolidin -1- yl ]- 6,7,8,9- tetrahydro -5 H -benzo [7] annen -2- yl ]-1 H -pyrazolo [3,4- b ] pyridin - 3- yl } phenyl ) pyra Azine

The title compound was prepared in an analogous manner to Example 2 from appropriate starting materials. ¹ H NMR (400 MHz, chloroform- d ) δ 13.21 (bs, 1H), 8.91 (d, J = 2.0 Hz, 1H), 8.50 (d, J = 2.1 Hz, 1H), 8.42 – 8.36 (m, 1H ), 8.16 – 8.08 (m, 2H), 7.78 – 7.70 (m, 2H), 7.35 (dq, J = 4.0, 2.0 Hz, 2H), 7.20 (d, J = 8.3 Hz, 1H), 3.25 (bs, 4H), 2.94 (bs, 1H), 2.67 (d, J = 0.7 Hz, 4H), 2.64 – 2.45 (m, 5H), 1.90 (dt, J = 20.4, 11.8 Hz, 3H), 1.74 (d, J = 6.1 Hz, 2H), 1.47 (bs, 3H), 1.06 (d, J = 33.1 Hz, 5H). ESI MS [M+H] ⁺ for C ₃₅ H ₃₉ N ₆ , calculated 543.3, found 543.3. Example 189 : 3,5- dimethyl -2-(4-{5-[(7 S )-7-( pyrrolidin -1- yl )-6,7,8,9- tetrahydro - 5H - Benzo [7] annen -2- yl ]-1 H -pyrazolo [3,4- b ] pyridin -3- yl } phenyl ) pyrazine

The title compound was prepared in an analogous manner to Example 2 from appropriate starting materials. ¹ H NMR (400 MHz, chloroform- d ) δ 13.08 (bs, 1H), 8.89 (d, J = 2.0 Hz, 1H), 8.51 (d, J = 2.1 Hz, 1H), 8.41 – 8.36 (m, 1H ), 8.16 – 8.07 (m, 2H), 7.78 – 7.70 (m, 2H), 7.42 – 7.34 (m, 2H), 7.22 (d, J = 8.3 Hz, 1H), 3.11 – 2.94 (m, 2H), 2.75 (q, J = 12.9 Hz, 7H), 2.67 (d, J = 0.6 Hz, 3H), 2.59 (s, 3H), 2.17 (d, J = 19.6 Hz, 2H), 1.84 (s, 4H), 1.64 (t, J = 11.3 Hz, 2H). ESI MS [M+H] ⁺ for C ₃₃ H ₃₅ N ₆ , calculated 515.3, found 515.3. Example 190 : 6-[( 7S )-2-{3-[4-(3,5- dimethylpyrazin- 2- yl ) phenyl ] -1H - pyrazolo [3,4- b ] pyridin -5- yl }-6,7,8,9 - tetrahydro - 5H - benzo [7] annen -7- yl ]-3- oxa -6- azabicyclo [3.1.1] Heptane

The title compound was prepared in an analogous manner to Example 2 from appropriate starting materials. ¹ H NMR (400 MHz, chloroform- d ) δ 12.57 (s, 1H), 8.85 (d, J = 2.0 Hz, 1H), 8.51 (d, J = 2.0 Hz, 1H), 8.38 (t, J = 0.7 Hz, 1H), 8.15 – 8.07 (m, 2H), 7.78 – 7.70 (m, 2H), 7.38 (d, J = 6.6 Hz, 2H), 7.24 – 7.21 (m, 1H), 4.31 (d, J = 10.7 Hz, 2H), 3.74 (d, J = 10.7 Hz, 2H), 3.67 (d, J = 6.1 Hz, 2H), 3.32 – 3.22 (m, 1H), 3.05 – 2.91 (m, 2H), 2.85 ( q, J = 12.7, 12.3 Hz, 2H), 2.67 (d, J = 0.6 Hz, 3H), 2.59 (s, 4H), 2.01 – 1.90 (m, 2H), 1.85 (d, J = 8.3 Hz, 1H ), 1.38 (q, J = 11.4 Hz, 2H). ESI MS [M+H] ⁺ for C ₃₄ H ₃₅ N ₆ O, calculated 543.3, found 543.3. Example 191 : 6-[( 7S )-2-{3-[4-(3,6- dimethylpyridin -2- yl )-3- methylphenyl ] -1H - pyrrolo [2, 3- b ] Pyridin -5- yl }-6,7,8,9 - tetrahydro - 5H - benzo [7] annen -7- yl ]-3- oxa -6- azabicyclo [3.1 .1] heptane

The title compound was prepared in an analogous manner to Example 1 from appropriate starting materials. ¹ H NMR (400 MHz, chloroform- d ) δ 11.08 – 11.03 (m, 1H), 8.59 (d, J = 2.0 Hz, 1H), 8.38 (d, J = 2.0 Hz, 1H), 7.56 – 7.44 (m , 3H), 7.42 – 7.28 (m, 3H), 7.22 (dd, J = 15.2, 8.0 Hz, 2H), 7.07 (d, J = 7.8 Hz, 1H), 4.30 (d, J = 10.8 Hz, 2H) , 3.74 (d, J = 10.8 Hz, 2H), 3.70 (d, J = 6.0 Hz, 2H), 3.31 – 3.21 (m, 1H), 2.97 (td, J = 14.0, 8.5 Hz, 2H), 2.83 ( q, J = 14.0, 13.5 Hz, 2H), 2.61 (s, 4H), 2.12 (d, J = 6.4 Hz, 6H), 1.93 (s, 2H), 1.85 (d, J = 8.3 Hz, 1H), 1.38 (p, J = 10.6 Hz, 2H). ESI MS [M+H] ⁺ for C ₃₇ H ₃₉ N ₄ O, calculated 555.3, found 555.3. Example 192 : 2-[5- methyl -6-(4-{5-[(7 S )-7-{3- oxa- 6- azabicyclo [3.1.1] hept -6- yl }- 6,7,8,9- tetrahydro -5 H -benzo [7] annen -2- yl ]-1 H -pyrazolo [3,4- b ] pyridin - 3- yl } phenyl ) pyridine -2- yl ] propan -2- ol

The title compound was prepared in an analogous manner to Example 2 from appropriate starting materials. ¹ H NMR (400 MHz, chloroform- d ) δ 12.83 (s, 1H), 8.86 (d, J = 2.0 Hz, 1H), 8.53 (d, J = 2.0 Hz, 1H), 8.15 – 8.07 (m, 2H ), 7.79 – 7.71 (m, 2H), 7.66 – 7.58 (m, 1H), 7.39 (d, J = 6.7 Hz, 2H), 7.23 (dd, J = 9.2, 8.1 Hz, 2H), 5.50 (s, 1H), 4.32 (d, J = 10.8 Hz, 2H), 3.81 – 3.70 (m, 4H), 3.34 – 3.24 (m, 1H), 2.97 (td, J = 14.0, 8.5 Hz, 2H), 2.85 (q , J = 12.8, 12.2 Hz, 2H), 2.67 (d, J = 7.9 Hz, 1H), 2.43 (d, J = 0.6 Hz, 3H), 1.97 (d, J = 11.6 Hz, 2H), 1.87 (d , J = 8.4 Hz, 1H), 1.56 (s, 6H), 1.43 (d, J = 11.8 Hz, 2H). ESI MS [M+H] ⁺ for C ₃₇ H ₄₀ N ₅ O ₂ , calculated 586.3, found 586.3. Example 193 : 6-[( 7S )-2-{3-[5-(3- methylpyridin -2- yl ) pyrazin -2- yl ] -1H - pyrazolo [3,4- b ] pyridin -5- yl }-6,7,8,9 - tetrahydro - 5H - benzo [7] annen -7- yl ]-3- oxa -6- azabicyclo [3.1.1] Heptane

The title compound (citrate salt) was prepared in an analogous manner to Example 17 from appropriate starting materials. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.43 (d, J = 1.5 Hz, 1H), 9.26 (d, J = 1.5 Hz, 1H), 8.95 (d, J = 2.2 Hz, 1H), 8.91 (d, J = 2.2 Hz, 1H), 8.57 (ddd, J = 4.7, 1.7, 0.6 Hz, 1H), 7.80 (ddd, J = 7.8, 1.7, 0.8 Hz, 1H), 7.59 (s, 1H), 7.52 (d, J = 7.7 Hz, 1H), 7.42 (dd, J = 7.7, 4.7 Hz, 1H), 7.30 (d, J = 7.8 Hz, 1H), 4.26 (bs, 3H), 3.87 (bs, 2H ), 2.98 – 2.82 (m, 4H), 2.56 (d, J = 3.1 Hz, 4H), 2.52 (s, 2H), 2.09 – 1.93 (m, 3H), 1.21 – 1.10 (m, 2H). ESI MS [M+H] ⁺ for C ₃₂ H ₃₂ N ₇ O, calculated 530.3, found 530.3. Example 194 : 6-[(7 S )-2-[3-(4-{2 H ,3 H -[1,4] dioxo [2,3-c] pyridin -5- yl } phenyl ) -1 H -pyrrolo [2,3- b ] pyridin -5- yl ]-6,7,8,9- tetrahydro -5 H -benzo [7] annen -7- yl ]-3- oxo Hetero -6- azabicyclo [3.1.1] heptane

The title compound was prepared in an analogous manner to Example 1 from appropriate starting materials. ¹ H NMR (400 MHz, chloroform- d ) δ 10.17 (d, J = 2.4 Hz, 1H), 8.60 (d, J = 2.0 Hz, 1H), 8.42 (dd, J = 2.1, 0.5 Hz, 1H), 8.14 (d, J = 5.3 Hz, 1H), 8.04 – 7.97 (m, 2H), 7.77 – 7.69 (m, 2H), 7.59 (d, J = 2.4 Hz, 1H), 7.38 (dq, J = 3.8, 2.0 Hz, 2H), 7.20 (d, J = 8.2 Hz, 1H), 6.79 (d, J = 5.3 Hz, 1H), 4.41 – 4.33 (m, 4H), 4.32 – 4.25 (m, 2H), 3.75 – 3.67 (m, 2H), 3.66 – 3.61 (m, 2H), 3.28 – 3.19 (m, 1H), 3.03 – 2.90 (m, 2H), 2.89 – 2.77 (m, 2H), 2.58 – 2.51 (m, 1H ), 1.97 – 1.88 (m, 2H), 1.85 – 1.78 (m, 1H), 1.38 – 1.27 (m, 2H). ESI MS [M+H] ⁺ for C ₃₆ H ₃₅ N ₄ O ₃ , calculated 571.3, found 571.2. Example 195 : 6-[( 7S )-2-{3-[4-(4,6- dimethylpyridin -3- yl ) phenyl ] -1H - pyrazolo [3,4- b ] Pyridin -5- yl }-6,7,8,9 - tetrahydro - 5H - benzo [7] annen -7- yl ]-3- oxa -6- azabicyclo [3.1.1] heptan alkyl

The title compound was prepared in an analogous manner to Example 2 from appropriate starting materials. ¹ H NMR (400 MHz, chloroform- d ) δ 13.85 (s, 1H), 8.83 (d, J = 2.0 Hz, 1H), 8.49 (d, J = 2.0 Hz, 1H), 8.39 (s, 1H), 8.10 – 8.02 (m, 2H), 7.48 – 7.40 (m, 2H), 7.35 (dq, J = 4.2, 2.0 Hz, 2H), 7.19 (d, J = 8.3 Hz, 1H), 7.09 – 7.03 (m, 1H), 4.34 – 4.24 (m, 2H), 3.73 (dt, J = 10.6, 1.6 Hz, 2H), 3.68 (d, J = 6.1 Hz, 2H), 3.26 (td, J = 9.9, 4.4 Hz, 1H ), 3.01 – 2.74 (m, 4H), 2.57 (s, 4H), 2.28 (d, J = 0.7 Hz, 3H), 2.00 – 1.89 (m, 2H), 1.84 (d, J = 8.3 Hz, 1H) , 1.37 (q, J = 11.4 Hz, 2H). ESI MS [M+H] ⁺ for C ₃₅ H ₃₆ N ₅ O, calculated 542.3, found 542.3. Example 196 : 6-[(7 S )-2-{3-[4-(4,6- dimethylpyridin -3- yl ) phenyl ]-1 H -pyrrolo [2,3- b ] pyridine -5- yl }-6,7,8,9 - tetrahydro - 5H - benzo [7] annen -7- yl ]-3- oxa -6- azabicyclo [3.1.1] heptane

The title compound was prepared in an analogous manner to Example 1 from appropriate starting materials. ¹ H NMR (400 MHz, chloroform- d ) δ 10.88 – 10.82 (m, 1H), 8.62 (d, J = 2.1 Hz, 1H), 8.43 (d, J = 2.1 Hz, 1H), 8.39 (s, 1H ), 7.79 – 7.71 (m, 2H), 7.62 (d, J = 2.4 Hz, 1H), 7.45 – 7.35 (m, 4H), 7.20 (d, J = 8.3 Hz, 1H), 7.10 – 7.05 (m, 1H), 4.29 (d, J = 10.6 Hz, 2H), 3.72 (d, J = 10.7 Hz, 2H), 3.63 (d, J = 6.1 Hz, 2H), 3.29 – 3.19 (m, 1H), 2.97 ( td, J = 15.5, 7.8 Hz, 2H), 2.84 (q, J = 13.6, 13.1 Hz, 2H), 2.56 (s, 4H), 2.32 (d, J = 0.6 Hz, 3H), 1.94 (d, J = 8.7 Hz, 2H), 1.83 (d, J = 8.2 Hz, 1H), 1.31 (q, J = 10.6, 10.1 Hz, 2H). ESI MS [M+H] ⁺ for C ₃₆ H ₃₇ N ₄ O, calculated 541.3, found 541.3. Example 197 : 3- methyl -2-(6-{5-[(7 S )-7-{3- oxa -6- azabicyclo [3.1.1] hept -6- yl }-6,7 ,8,9- tetrahydro -5 H -benzo [7] annen -2- yl ]-1 H -pyrrolo [2,3- b ] pyridin - 3- yl } pyridin -3- yl ) benzyl Nitrile

The title compound was prepared in an analogous manner to Example 9 from appropriate starting materials. ¹ H NMR (400 MHz, chloroform- d ) δ 11.46 (s, 1H), 8.96 (d, J = 2.1 Hz, 1H), 8.62 (d, J = 2.1 Hz, 1H), 8.60 (dd, J = 2.4 , 0.9 Hz, 1H), 8.04 (d, J = 2.3 Hz, 1H), 7.80 (dd, J = 8.2, 0.9 Hz, 1H), 7.67 (dd, J = 8.2, 2.3 Hz, 1H), 7.62 (ddd , J = 7.7, 1.4, 0.7 Hz, 1H), 7.52 (ddd, J = 7.8, 1.4, 0.7 Hz, 1H), 7.47 – 7.41 (m, 2H), 7.38 (t, J = 7.8 Hz, 1H), 7.23 – 7.19 (m, 1H), 4.30 (d, J = 10.6 Hz, 2H), 3.71 (d, J = 10.8 Hz, 2H), 3.64 (d, J = 6.1 Hz, 2H), 3.29 – 3.19 (m , 1H), 3.04 – 2.93 (m, 2H), 2.90 – 2.77 (m, 2H), 2.54 (td, J = 7.6, 7.1, 3.6 Hz, 1H), 2.25 (d, J = 0.8 Hz, 3H), 2.02 – 1.91 (m, 2H), 1.83 (d, J = 8.2 Hz, 1H), 1.40 – 1.21 (m, 2H). ESI MS [M+H] ⁺ for C ₃₆ H ₃₄ N ₅ O, calculated 552.3, found 552.3. Example 198 : 1-[6- methyl -2-(4-{5-[(7 S )-7-{3- oxa- 6- azabicyclo [3.1.1] hept -6- yl }- 6,7,8,9- tetrahydro -5 H -benzo [7] annen -2- yl ]-1 H -pyrazolo [3,4- b ] pyridin - 3- yl } phenyl ) pyridine -3- yl ] pyrrolidin -2- one

The title compound was prepared in an analogous manner to Example 2 from appropriate starting materials. ¹ H NMR (400 MHz, chloroform- d ) δ 12.35 (s, 1H), 8.86 (d, J = 2.0 Hz, 1H), 8.50 (d, J = 2.0 Hz, 1H), 8.12 – 8.04 (m, 2H ), 7.79 – 7.71 (m, 2H), 7.59 (d, J = 8.1 Hz, 1H), 7.38 (dq, J = 3.1, 2.0 Hz, 2H), 7.23 (dd, J = 9.7, 8.2 Hz, 2H) , 4.31 (d, J = 10.8 Hz, 2H), 3.74 (d, J = 10.8 Hz, 2H), 3.68 (d, J = 6.1 Hz, 2H), 3.33 – 3.25 (m, 3H), 3.04 – 2.94 ( m, 2H), 2.86 (q, J = 13.7 Hz, 2H), 2.63 (s, 3H), 2.58 (q, J = 6.8 Hz, 1H), 2.48 (t, J = 8.0 Hz, 2H), 1.96 ( p, J = 7.6 Hz, 4H), 1.85 (d, J = 8.3 Hz, 1H), 1.37 (q, J = 11.7 Hz, 2H). ESI MS [M+H] ⁺ for C ₃₈ H ₃₉ N ₆ O ₂ , calculated 611.3, found 611.3. Biological Example Measuring Intracellular Binding of Axl Inhibitors

The Axl NanoBRET ^TM intracellular kinase assay (Promega, N2540) was performed according to the manufacturer's recommendations. Briefly, HEK-293 cell lines were transiently transfected with the Axl-NanoLuc fusion vector (Promega, NV1071) using Fugene HD transfection reagent (Promega, E2311) one day before the experiment as recommended by the manufacturer.

On the day of assay, cells were collected and resuspended in Opti-MEM medium (ThermoFisher, 31985070) at a concentration of 2e5 cells/mL. Test compounds were serially diluted at 200 nL in 100% DMSO and dispensed into white 384-well polystyrene plates. Then add 40µL of resuspended cells to each well to obtain final conditions of 8K cells/well, .5% DMSO. After a one-hour compound preincubation at 37°C and 5% _CO2 , cells were further incubated with 0.35 µM K-5 NanoBRET tracer for two hours at 37°C and 5% _CO2 . Prepare 20 ml of 3X substrate plus inhibitor solution according to the kit manual and add to cells, followed by 30 seconds pulse centrifugation. The plate was then immediately read using an Envision (Perkin Elmer) plate reader. The BRET signal is measured by taking the ratio of emission readings at 610nm and 450nm. Compound binding is based on the reduction in BRET signal caused by the displacement of the K-5 tracer. DMSO-treated activity was used as a neutral control and normalized to 100% activity, and 20 µM of CEP-40783 control compound, which achieved 100% inhibition, was used as a positive control and normalized to 0% activity. The _IC50 value of the compound was determined by 4-parameter nonlinear regression fitting of percent activity in GraphPad Prism software. Values are reported in Table 1 (Cell Binding). Measuring the Potency of Biochemical Compounds with Axl Inhibitors

Purified recombinant human AXL, TYRO3 and MER proteins were purchased from Invitrogen™. 10 nM AXL, 2 nM TYRO3 or MER were mixed with different concentrations of compounds in 50 mM HEPES, pH 7.4, 10 mM MgCl ₂ , 0.01% BSA, 1 mM DTT and 2% DMSO in a 384-well microplate in a total volume of 20 µl. Incubate in well plate (Corning™ #3640) for 1 h at RT. AXL, TYRO3, and MER enzymatic reactions were initiated by transferring 10 µl of the enzyme and compound mixture to 10 µl of 1.6 µM TK Substrate-Biotin (Biotin) in a 384-well microplate (Corning™ #3640) at RT. HTRF® KinEASE-TK Kit, Cisbio) and preincubated in 50 mM HEPES, pH 7.4, 10 mM MgCl ₂ , 0.01% BSA, 1400 µM ATP in 1 mM DTT, giving final reaction conditions: 5 nM AXL, 1 nM TYRO3 or MER, 800 nM TK substrate-biotin and 700 µM ATP in 50 mM HEPES, pH 7.4, 10 mM MgCl ₂ , 0.01% BSA, 1 mM DTT and 1% DMSO, containing different concentrations of compounds. After incubation for 2 h at RT, 10 µl of the detection mixture (400 nM Streptavidin-XL665, 200-fold diluted TK antibody) was transferred to a white 384-well microplate (Perkin Elmer, OptiPlate 384). - Cryptate and detection buffer, HTRF® KinEASE-TK Kit, Cisbio) are used to perform AXL, TYRO3 and MER enzymatic reactions. After incubation for 1 h at RT, the plate was placed in a plate reader (Evision) to read HTRF at 665/620 nm (acceptor/donor). DMSO blank (MIN inhibition = 100% activity) was used as a negative control. Create a positive control by adding 5 µl of enzyme and DMSO mixture to 10 µl of detection mixture, followed by 5 µl of TK substrate-biotin and ATP mixture (MAX inhibition = 0% activity). To calculate the percent activity, equation 1 was used. The ratio _665/620 is the value for a given compound concentration: The compound concentration that results in a 50% loss of enzyme activity ( IC ₅₀ ) was calculated by GraphPad Prism using Equation 2, where N is the Hill coefficient: Values are reported in Table 1 (Biochemical Potency). Measurement of Axl Phosphorylation Inhibition

Dose-response assay in S-Bio PrimeSurface® 3D cultures: Ultra-low Attachment Plates: 384-well, U-bottom (#MS-9384UZ), containing 400 nL of 22 series of 2x compound dilutions, using Bravo and Echo . ELISA assays were performed on Pierce™ Streptavidin-coated high-capacity 384-well white plates (Thermofisher Cat. No. 15505). Plates were coated with 50 µl/well of biotinylated phosphotyrosine mouse mAb (Cell Signaling Technology, 9417s) overnight at 4°C.

HEK293T cells were grown in DMEM containing 10% FBS, 1% Pen/Strep, and 1% G-Max. Cells were transiently transfected with 6.8 µg of NanoLuc-labeled AXL plasmid DNA and 8 µg of vector DNA using FuGENE® HD Transfection Reagent (Promega) one day before the assay according to the manufacturer's instructions. On the day of assay, transfected cells were harvested and resuspended in OptiMEM. 70,000 cells/well were added to assay plates containing compounds. After gentle mixing and brief rotation, the plate was incubated at 37°C. After 1 h, cells were lysed, centrifuged briefly and shaken at 300 rpm for 30 min. Meanwhile, the antibody-coated plates were brought to room temperature and then washed ten times in PBS containing 0.05% Tween 20 (ELISA wash buffer). Transfer 50 µl/well of cell lysate to the ELISA plate and shake for 2 hours. After washing again with ELISA wash buffer, dilute the sample with 25 µl PBS. Captured NanoLuc-labeled p-AXL was detected using the Nano-Glo® Luciferase Assay System (Promega) and the manufacturer's instructions. Use an Envision plate reader to measure the luminescence signal. IC50 values were determined by fitting the data to a standard 4-parameter logistic equation. Values are reported in Table 1 (p-AXL inhibition). Table 1 : Example-specific biochemical and cellular potency and inhibition of Axl phosphorylation ( _IC50 : + indicates >1 µM, ++ indicates 100 nM to 1 µM, +++ indicates <100 nM) Example cell binding p-AXL inhibition Biochemical potency AXL p-AXL (vehicle) AXL MER TYRO3 1 +++ +++ +++ +++ +++ 2 +++ +++ +++ ++ +++ 3 +++ +++ +++ +++ 4 ++ +++ ++ ++ 5 +++ +++ ++ +++ 6 +++ +++ ++ ++ 7 +++ +++ ++ +++ 8 ++ +++ 9 +++ +++ ++ 10 +++ +++ +++ ++ +++ 11 ++ +++ + + 12 +++ +++ +++ ++ ++ 13 +++ ++ +++ + + 14 +++ +++ ++ +++ 15 ++ +++ 16 +++ +++ 17 +++ +++ ++ 18 +++ +++ 19 ++ +++ 20 +++ +++ twenty one +++ +++ ++ +++ twenty two +++ +++ +++ +++ twenty three +++ +++ ++ +++ twenty four ++ +++ 25 +++ +++ 26 +++ +++ ++ ++ 27 +++ +++ 28 ++ +++ ++ +++ 29 ++ +++ ++ ++ 30 ++ + + +++ 31 ++ +++ + + 32 ++ +++ ++ ++ 33 ++ +++ ++ ++ 34 +++ +++ 35 +++ +++ 36 + +++ 37 +++ +++ 38 +++ +++ 39 +++ +++ 40 ++ +++ ++ ++ 41 ++ ++ +++ ++ + 42 ++ +++ ++ ++ 43 ++ +++ ++ ++ 44 +++ ++ +++ ++ ++ 45 +++ ++ +++ + + 46 +++ +++ +++ ++ ++ 47 +++ +++ +++ +++ +++ 48 +++ +++ +++ ++ ++ 49 +++ +++ +++ +++ +++ 50 +++ +++ ++ ++ 51 +++ +++ +++ +++ 52 +++ +++ ++ ++ 53 +++ +++ ++ ++ 54 +++ +++ + ++ 55 +++ +++ + 56 +++ +++ ++ ++ 57 +++ +++ ++ ++ 58 +++ +++ ++ ++ 59 ++ +++ ++ ++ 60 ++ +++ 61 +++ +++ 62 +++ +++ 63 +++ +++ 64 +++ +++ 65 +++ +++ 66 +++ +++ 67 ++ +++ 68 +++ +++ 69 ++ +++ 70 +++ +++ 71 +++ +++ 72 ++ +++ 73 ++ +++ 74 ++ +++ 75 +++ +++ 76 +++ +++ 77 +++ +++ ++ +++ 78 +++ +++ +++ +++ 79 +++ +++ ++ 80 +++ +++ +++ ++ 81 +++ +++ 82 +++ +++ 83 +++ +++ 84 + +++ 85 +++ +++ ++ ++ 86 ++ +++ ++ ++ 87 ++ +++ ++ ++ 88 ++ +++ ++ ++ 89 ++ +++ ++ ++ 90 +++ +++ +++ ++ ++ 91 +++ ++ +++ ++ ++ 92 +++ +++ +++ ++ +++ 93 +++ ++ +++ ++ ++ 94 +++ ++ +++ + + 95 +++ +++ +++ +++ +++ 96 +++ +++ ++ +++ 97 + +++ + + 98 ++ +++ + + 99 +++ +++ ++ ++ 100 +++ +++ + ++ 101 +++ +++ ++ +++ 102 +++ +++ ++ +++ 103 + +++ + + 104 +++ +++ ++ ++ 105 +++ +++ +++ +++ 106 +++ +++ 107 +++ +++ 108 +++ +++ 109 +++ +++ +++ ++ ++ 110 +++ +++ +++ ++ +++ 111 +++ +++ +++ +++ +++ 112 +++ +++ +++ +++ +++ 113 +++ +++ ++ ++ 114 +++ +++ ++ ++ 115 ++ +++ ++ + 116 ++ +++ ++ ++ 117 ++ +++ + ++ 118 +++ +++ ++ +++ 119 +++ +++ +++ +++ 120 +++ +++ ++ +++ 121 +++ +++ +++ +++ 122 +++ +++ ++ +++ 123 +++ +++ +++ +++ 124 +++ +++ +++ +++ 125 +++ +++ +++ +++ 126 ++ +++ ++ 127 +++ +++ ++ +++ 128 +++ +++ ++ +++ 129 +++ +++ +++ +++ 130 +++ +++ +++ +++ 131 ++ +++ +++ +++ 132 +++ +++ +++ +++ 133 +++ +++ 134 +++ +++ 135 +++ +++ 136 +++ +++ 137 +++ +++ 138 +++ +++ 139 +++ +++ 140 +++ +++ 141 +++ +++ 142 +++ +++ 143 ++ +++ 144 +++ +++ 145 ++ +++ 146 ++ +++ 147 +++ +++ 148 ++ +++ 149 +++ +++ 150 ++ +++ 151 +++ +++ 152 +++ +++ 153 +++ +++ 154 +++ +++ +++ ++ ++ 155 +++ ++ +++ + ++ 156 +++ ++ +++ ++ ++ 157 ++ +++ + + 158 ++ ++ +++ + + 159 ++ ++ +++ ++ ++ 160 ++ +++ ++ ++ 161 ++ +++ ++ ++ 162 + +++ + + 163 +++ +++ +++ +++ +++ 164 +++ +++ +++ ++ +++ 165 +++ +++ +++ ++ +++ 166 +++ +++ +++ ++ +++ 167 +++ +++ +++ ++ +++ 168 +++ ++ +++ ++ ++ 169 +++ +++ +++ +++ +++ 170 +++ ++ +++ ++ ++ 171 +++ +++ +++ ++ ++ 172 +++ +++ +++ +++ +++ 173 +++ +++ +++ +++ +++ 174 +++ +++ +++ +++ +++ 175 +++ +++ +++ ++ ++ 176 +++ +++ +++ +++ +++ 177 +++ +++ ++ ++ 178 +++ +++ ++ ++ 179 ++ +++ ++ ++ 180 +++ +++ ++ +++ 181 ++ +++ ++ ++ 182 +++ +++ ++ +++ 183 +++ +++ ++ +++ 184 +++ +++ 185 ++ +++ 186 ++ +++ +++ +++ 187 +++ +++ ++ +++ 188 +++ +++ 189 ++ +++ 190 ++ +++ 191 +++ +++ 192 ++ +++ 193 +++ +++ 194 +++ +++ 195 ++ +++ 196 ++ +++ 197 ++ +++ 198 ++ +++

Specific embodiments of the disclosure are described herein, including the best mode known to the inventors for carrying out the disclosure. Variations in the disclosed embodiments may become apparent to those skilled in the art upon reading the foregoing description, and it is expected that such variations will be appropriately adopted by those skilled in the art. Accordingly, this disclosure is intended to be practiced otherwise than as specifically described herein, and this disclosure includes all modifications and equivalents of the subject matter recited in the appended claims to the extent permitted by applicable law. Furthermore, any combination of the above elements and all possible variations thereof are encompassed by this disclosure unless otherwise indicated herein or otherwise clearly contradicted by context.

All publications, patent applications, accession numbers, and other references cited in this specification are herein incorporated by reference as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference.

Claims (87)

A compound represented by formula (I) or a pharmaceutically acceptable salt thereof, (I) Among them: X is CR ⁵ or N; G ¹ is N or CR ^G1 ; G ² is CR ^G2 or N; G ³ is CR ^G3 or N; G ⁴ is CR ^G4 or N; G ⁵ is CR ^G5 or N; ^RG1 is selected from the group consisting of H, C _1-3 alkyl, halogen, C _1-3 haloalkyl and CN; each ^RG2 , ^RG3 , ^RG4 and ^RG5 is independently selected from the group consisting of Group: H, halo, CN, C _1-7 alkyl, C _3-7 cycloalkyl, C _1-3 haloalkyl, -OC _1-3 alkyl, -OC _1-3 haloalkyl, -NR ^a R ^b and a 5 to 8-membered heterocycloalkyl group having 1 to 3 heteroatom ring vertices selected from the group consisting of O, N and S, and wherein the cycloalkyl group and the heterocycloalkyl group are separated by 0 to 3 Substituted with a group independently selected from the following: halo, CN, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 hydroxyalkyl, -OC _1-4 alkyl and OH; A It is a fused ring selected from the group consisting of: cycloheptane, cyclohexane, cyclopentane, azepane, 1,4-oxazepane, 1,4-diazepane Alkane, oxepane, tetrahydropyran, piperidine, bicyclo[4.2.1]nonane, bicyclo[4.1.1]octane, spiro[4.6]undecane, 1-azaspiro[4.6] Undecane and cyclooctane, each of which is substituted by 1 to 4 R ² and further substituted by 0 or 1 pendant oxygen group (=O) located on the carbon atom adjacent to the nitrogen atom; R ¹ is selected from the following Group: phenyl and 5 to 6-membered heteroaryl having 1-3 heteroatom ring vertices selected from the group consisting of O, N and S, and each phenyl and heteroaryl is separated by one R ^1a and 0 -3 R ³ substitutions; R ^1a is selected from the group consisting of: phenyl and a 5- to 6-membered heteroaryl group having 1 to 3 heteroatom ring vertices selected from the group consisting of O, N and S, wherein the N atoms are optionally oxidized when present, and each phenyl and heteroaryl group is substituted by 0-4 R ⁴ ; each R ² is independently selected from the group consisting of: C _1-7 alkyl, C _{3- 7} alkenyl, C _3-7 alkynyl, C _3-7 cycloalkyl, -Y ¹ -OC _1-7 alkyl, -Y ¹ -OC _3-7 cycloalkyl, -NR ^a R ^b , -C (O)-C _1-7 alkyl, -C(O)-C _3-7 cycloalkyl, -S(O) ₂ -C _1-7 alkyl, -S(O) ₂ -C _3-7 Cycloalkyl, -C(O)NR ^a R ^b , 5 to 8-membered heterocycloalkyl, -NR ^a -(5 to 8-membered heterocycloalkyl), -C(O)-(5 to 8-membered heterocycloalkyl) Cycloalkyl), -X ¹ -5 to 8-membered heterocycloalkyl and -OX ¹ -(5 to 8-membered heterocycloalkyl), wherein the heterocycloalkyl has 1-3 selected from O, N and The heteroatom ring vertex of the group consisting of S, in which each cycloalkyl and heterocycloalkyl is substituted by 0-3 groups independently selected from the following: halo, CN, C _1-4 alkyl, C _{1 -4} haloalkyl, C _1-4 hydroxyalkyl, -OC _1-4 alkyl and OH; each R ³ is independently selected from the group consisting of: halogen, CN, C _1-7 alkyl, C _{2- 7} alkenyl, C _3-7 alkynyl, C _1-4 haloalkyl, C _1-4 hydroxyalkyl, C _1-4 halohydroxyalkyl, -OC _1-7 alkyl, -OC _1-6 halo Alkyl group, -NR ^a R ^b , -C(O)-NR ^a R ^b , -S(O) ₂ -NR ^a R ^b , -S(O)(NH)-C _1-7 Alkyl group, -S (O) ₂ -C _1-7 alkyl and -S(O) ₂ -C _1-7 haloalkyl; each R ⁴ is independently selected from the group consisting of: C _1-7 alkyl, halo, C _1-7 haloalkyl, -OC _1-7 alkyl, -OC _1-7 haloalkyl, CN, -C _1-7 alkylene-CN, hydroxyl, C _1-7 hydroxyalkyl, -C( O)NR ^a R ^b , C _3-7 cycloalkyl, -NR ^a -C(O)-C _1-7 alkyl, -NR ^a -C(O)-C _3-7 cycloalkyl, -NR ^a R ^b , -OC _1-4 alkylene group -OC _1-4 alkyl group, -O- (5 to 8 membered heteroatom ring vertices with 1 to 3 heteroatoms selected from the group consisting of O, N and S Cycloalkyl), -5 to 8-membered heterocycloalkyl having 1-3 heteroatom ring vertices selected from the group consisting of O, N and S, -S(O) ₂ -C _1-7 alkyl, -S(O) ₂ -C _3-7 cycloalkyl, -S(O) ₂ -NR ^a R ^b , -NR ^a -S(O) ₂ -C _1-7 alkyl and -NR ^a -S( O) ₂ -C _3-7 cycloalkyl, wherein each cycloalkyl and heterocycloalkyl is substituted by 0 to 2 groups independently selected from the group consisting of: C _1-4 alkyl, halo and Hydroxy; Or, two R ⁴ groups on the same ring vertex combine to form a side oxygen group (=O); or two R ⁴ groups on adjacent ring vertices combine to form a group with 1 to 2 selected from O, N and a 5- to 6-membered heterocycloalkyl group at the vertex of the heteroatom ring of the group consisting of S, wherein the 5- to 6-membered heterocycloalkyl group is substituted with 0 to 2 groups independently selected from the group consisting of: C _{1 -4} alkyl and halo; R ⁵ is selected from the group consisting of: H, C _1-4 alkyl and -NH ₂ ; each X ¹ is C _1-7 alkyl or C _3-7 cycloalkyl ; Each Y ¹ is C _2-7 alkylene group or C _3-7 cycloalkyl group; Each R ^a and R ^b are independently selected from the group consisting of: H, C _1-7 alkyl group, C _1-7 Haloalkyl, C _1-4 alkoxy C _1-4 alkyl, C _3-7 cycloalkyl, wherein the cycloalkyl is optionally substituted by -OC _1-3 alkyl; or R ^a and R ^b and The nitrogens to which they are attached together form a 4- to 8-membered heterocycloalkyl ring having 0-2 additional heteroatom ring vertices selected from the group consisting of O, N, and S, wherein the heterocycloalkyl ring has 0-3 Substituted with a group, each group is independently selected from halo, CN, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 hydroxyalkyl, -OC _1-4 alkyl and X ¹ -OC _1-3 alkyl and OH; or two groups on the same ring vertex combine to form a side oxygen group (=O). Such as the compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein: ^G3 is CR ^G3 , and R ^G3 is H; ^G4 is CR ^G4 and R ^G4 is H; and ^G5 is each CR ^G5 and R ^G5 series H. For example, the compound of claim 1 or claim 2 , or a pharmaceutically acceptable salt thereof, wherein G ¹ is N or CR ^G1 , and R ^G1 is H. The compound of any one of claims 1 to 3 , or a pharmaceutically acceptable salt thereof, wherein ^G2 is CR ^G2 and ^RG2 is H. The compound of any one of claims 1 to 4 , or a pharmaceutically acceptable salt thereof, wherein X is CR ⁵ and R ⁵ is H. The compound of any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, wherein A has a formula selected from the group consisting of: , and , each of which is substituted by 1 to 4 R ² . For example, the compound of claim 6 or a pharmaceutically acceptable salt thereof, wherein A has the formula: or . For example, the compound of any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof, wherein one R ² is -NR ^a R ^b . For example, the compound of any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, wherein one R ² is selected from the group consisting of: , , , , , and . For example, the compound or pharmaceutically acceptable salt of claim 9 , wherein one R ² is . Such as the compound of any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from the group consisting of: phenyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, oxazinyl Diazolyl and pyrazolyl, wherein R ¹ is substituted by one R ^1a and 0-2 R ³ . For example, the compound of claim 11 or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from the group consisting of: , , , , , , , , and , where the subscript p is 0 or 1. For example, the compound of claim 11 or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from the group consisting of: and , where the subscript p is 0 or 1. Such as the compound of any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof, wherein each R ³ when present is independently selected from the group consisting of: halogen, CN, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 hydroxyalkyl, C _1-4 halohydroxyalkyl, -OC _1-4 alkyl, -OC _1-4 haloalkyl, -NR ^a R ^b , -C ( O)-NR ^a R ^b , -S(O) ₂ -NR ^a R ^b , -S(O)(NH)-C _1-4 alkyl, -S(O) ₂ -C _1-4 alkyl and -S(O) ₂ -C _1-4 haloalkyl. For example, the compound of claim 14 or a pharmaceutically acceptable salt thereof, wherein each R ³ when present is independently selected from the group consisting of: halogen, C _1-4 alkyl and -OC _1-4 alkyl. For example, the compound of claim 14 or a pharmaceutically acceptable salt thereof, wherein each R ³ when present is independently selected from the group consisting of: fluorine, chlorine, methyl and methoxy. The compound of any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof, wherein R ^1a is selected from the group consisting of: pyrazolyl, imidazolyl, triazolyl, thiazolyl, oxazolyl, Pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyridyl N-oxide and phenyl, wherein R ^1a is substituted by 0 to 3 R ^4's . For example, the compound of claim 17 or a pharmaceutically acceptable salt thereof, wherein R ^1a is selected from the group consisting of: , , , , , , , , , , , , , , , , , , The subscript q is 0, 1 or 2. For example, the compound of claim 17 or a pharmaceutically acceptable salt thereof, wherein R ^1a is selected from the group consisting of: and The subscript q is 0, 1 or 2. For example, the compound of claim 17 or a pharmaceutically acceptable salt thereof, wherein R ^1a is selected from the group consisting of: , and . The compound of any one of claims 1 to 20 or a pharmaceutically acceptable salt thereof, wherein each R ⁴ when present is independently selected from the group consisting of: C _1-4 alkyl, halo, C _{1 -4} haloalkyl, -OC _1-4 alkyl, -OC _1-4 haloalkyl, CN, -C _1-4 alkylene-CN, C _1-4 hydroxyalkyl, -C(O)NR ^a R ^b , C _3-7 cycloalkyl, -NR ^a -C(O)-C _3-7 cycloalkyl, -NR ^a R ^b , -OC _1-4 alkylene-OC _1-4 alkyl , -O- (5 to 6-membered heterocycloalkyl) having 1-3 heteroatom ring vertices selected from the group consisting of O, N and S, having 1-3 selected from the group consisting of O, N and S -5 to 8-membered heterocycloalkyl, -S(O) ₂ -C _1-4 alkyl and -S(O) ₂ -NR ^a R ^b at the vertex of the heteroatom ring of the group, in which each cycloalkyl and hetero Cycloalkyl is substituted with 0 to 2 groups selected from the group consisting of: C _1-4 alkyl, halo and hydroxyl. Such as the compound of claim 21 or a pharmaceutically acceptable salt thereof, wherein each R ⁴ when present is independently selected from the group consisting of: methyl, ethyl, fluorine, chlorine, difluoromethyl, trifluoromethyl base, CN, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, , , , , , , , , , , , , , , , , and . The compound of any one of claims 1 to 20 or a pharmaceutically acceptable salt thereof, wherein two R ⁴ groups on adjacent ring vertices are combined to form a compound having 1 to 2 selected from O, N and S. A 5- to 6-membered heterocycloalkyl group at the vertex of the heteroatom ring of the group, wherein the 5- to 6-membered heterocycloalkyl group is substituted with 0 to 2 groups independently selected from the group consisting of: C _1-4 alkyl base and halo group. The compound of claim 23 , wherein two R ⁴ groups on adjacent ring vertices combine to form a heterocycloalkyl group selected from the following: and wherein the heterocycloalkyl group is substituted with 0 to 2 groups independently selected from the group consisting of: C _1-4 alkyl and halo. For example, the compound of any one of claims 1 to 2 or 5 to 24 or a pharmaceutically acceptable salt thereof has a structure selected from formula (Ia) or formula (Ia1): (Ia), (Ia1). For example, the compound of any one of claims 1 to 2 , 5 , or 8 to 24 , or a pharmaceutically acceptable salt thereof, has a structure according to formula (Ib) or formula (Ib1): (Ib), (Ib1) Wherein for each of formula (Ib) and formula (Ib1), the subscript m is 0 or 1; and n is 0, 1 or 2, and each R ² can be the same or different. For example, the compound of claim 26 or its pharmaceutically acceptable salt has the structure of formula (If) or formula (If1): (If), (If1). Such as the compound of claim 26 or 27 , wherein m is 0. The compound of any one of claims 26 to 28 , wherein n is 0. For example, the compound of claim 1 or its pharmaceutically acceptable salt is selected from the group consisting of: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and . A compound represented by formula (II) or a pharmaceutically acceptable salt thereof, ( ^II ) wherein: to 4 R ² substituted; R ¹ is selected from the group consisting of: phenyl and 5 to 6 membered heteroaryl having 1 to 3 heteroatom ring vertices selected from the group consisting of O, N and S, and wherein Each phenyl and heteroaryl is substituted by one R ^1a and 0-3 R ³ ; R ^1a is selected from the group consisting of: phenyl and having 1-3 heteroatoms selected from the group consisting of O, N and S A 5- to 6-membered heteroaryl group at the ring apex, in which the N atom is optionally oxidized when present, and each phenyl and heteroaryl group is substituted by 0-4 R ⁴ ; each R ² is independently selected from the following: Group: C _1-7 alkyl, C _3-7 cycloalkyl, -Y ¹ -OC _1-7 alkyl, -NR ^a R ^b , 5 to 8 membered heterocycloalkyl and -NR ^a -(5 to 8-membered heterocycloalkyl), wherein the heterocycloalkyl has 1-3 heteroatom ring vertices selected from the group consisting of O, N and S, and wherein each cycloalkyl and heterocycloalkyl is separated by 0- 3 groups independently selected from the following groups substituted: C _1-4 alkyl and -OC _1-4 alkyl; Each R ³ is independently selected from the group consisting of: halogen, C _1-7 alkyl and -OC _1-7 alkyl; each R ⁴ is independently selected from the group consisting of: C _1-7 alkyl, halo, C _1-7 haloalkyl, -OC _1-7 alkyl, -OC _1-7 halo Alkyl, CN, -C _1-7 alkylene-CN, C _1-7 hydroxyalkyl, -C(O)NR ^a R ^b , C _3-7 cycloalkyl, -NR ^a -C(O) -C _3-7 cycloalkyl, -NR ^a R ^b , -OC _1-4 alkylene -OC _1-4 alkyl, having 1-3 heteroatom rings selected from the group consisting of O, N and S -O- (5 to 8 membered heterocycloalkyl) at the vertex, -5 to 8 membered heterocycloalkyl at the vertex having 1 to 3 heteroatoms selected from the group consisting of O, N and S, -S( O) ₂ -C _1-7 alkyl and -S(O) ₂ -NR ^a R ^b , wherein each cycloalkyl and heterocycloalkyl is substituted by 0 to 2 groups independently selected from the following groups: C _{1 -4} alkyl and hydroxyl; alternatively, two R ⁴ groups on adjacent ring vertices combine to form a 5 to 6 membered heterocycle with 1 to 2 heteroatom ring vertices selected from the group consisting of O, N and S Alkyl group, wherein the 5- to 6-membered heterocycloalkyl group is substituted by 0 to 2 C _1-4 alkyl groups; each X ¹ is a C _1-7 alkyl group; each Y ¹ is a C _2-7 alkyl group; Each R ^a and R ^b are independently selected from the group consisting of: H, C _1-7 alkyl, C _3-7 cycloalkyl, wherein the cycloalkyl is optionally substituted with -OC _1-3 alkyl; or R ^a and R ^b together with the nitrogen to which they are attached form a 4 to 8 membered heterocycloalkyl ring having 0 to 2 additional heteroatom ring vertices selected from the group consisting of O, N and S, wherein the heterocycloalkyl The base ring is substituted by 0-3 groups, each group is independently selected from C _1-4 alkyl, -OC _1-4 alkyl and X ¹ -OC _1-3 alkyl; or two on the same ring vertex groups combine to form a pendant oxygen group (=O). A pharmaceutical composition comprising a compound according to any one of claims 1 to 31 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. The pharmaceutical composition of claim 32 , wherein the composition contains 10 to 300 mg of the compound of any one of claims 1 to 31 or a pharmaceutically acceptable salt thereof. A method of treating cancer, fibrosis, viral infection or pain, the method comprising administering to an individual in need a compound as claimed in any one of claims 1 to 31 or a pharmaceutically acceptable salt thereof, or as claimed 32 or 33 pharmaceutical compositions. A method of treating a disease, condition or disorder that is at least partially mediated by AXL, the method comprising administering once daily to an individual in need thereof 10 to 300 mg of a compound of any one of claims 1 to 31 , or a pharmaceutical agent thereof An acceptable salt, or a pharmaceutical composition as claimed in claim 32 or 33 . The method of claim 34 or 35 , wherein the disease, condition or disorder is cancer. Such as the method of claim 36 , wherein the cancer is prostate cancer, colon cancer, rectal cancer, pancreatic cancer, cervical cancer, gastric cancer, endometrial cancer, uterine cancer, brain cancer, liver cancer, bladder cancer, ovarian cancer, fallopian tube cancer , peritoneal cancer, testicular cancer, head cancer, neck cancer, skin cancer (including melanoma and basal cancer), mesothelial lining cancer, leukocyte cancer (including lymphoma and leukemia), esophageal cancer, breast cancer, muscle cancer, Connective tissue cancer, intestinal cancer, lung cancer (including small cell lung cancer and non-small cell lung cancer), adrenal cancer, thyroid cancer, kidney cancer or bone cancer; or glioblastoma, mesothelioma, renal cell carcinoma, gastric cancer, Sarcoma (including Kaposi's sarcoma), choriocarcinoma, basal cell carcinoma of the skin, or testicular seminoma, or any combination thereof. The method of claim 36 , wherein the cancer is selected from the group consisting of skin cancer (e.g., melanoma), pancreatic cancer (e.g., pancreatic ductal adenocarcinoma), breast cancer (e.g., triple negative breast cancer), bladder cancer , liver cancer, lung cancer (e.g., non-small cell lung cancer), leukemia (e.g., acute myeloid leukemia or myelodysplasia syndrome), brain tumor (e.g., glioblastoma), ovarian cancer (e.g., epithelial ovarian cancer) (EOC), high-grade serous ovarian cancer (HGSOC) or platinum-resistant ovarian cancer (PROC)), renal cancer (eg, clear cell renal cell carcinoma), mesothelioma, and head and neck cancer (eg, head and neck squamous cell carcinoma) cancer). The method of claim 38 , wherein the cancer is acute myeloid leukemia, myeloid metaplasia syndrome, non-small cell lung cancer, ovarian cancer or clear cell renal cell carcinoma. The method of any one of claims 36 to 39 , wherein the cancer recurs or is resistant to radiotherapy, chemotherapy or immunotherapy. For example, claim 34 or 35 , wherein the disease, condition or disorder is a viral infection. The method of claim 41 , wherein the viral infection is caused by SARS-CoV-2, Ebola virus, monkeypox or Zika virus. The method of claim 34 or 35 , wherein the disease, condition or disorder is fibrosis. The method of claim 43 , wherein the fibrosis is renal fibrosis (eg, chronic kidney disease), intestinal fibrosis (eg, Crohn's disease), liver fibrosis (eg, chronic liver disease), or pulmonary fibrosis. Fibrosis (eg, idiopathic pulmonary fibrosis). The method of any one of claims 35 to 40 , further comprising administering to the individual at least one additional therapeutic agent. The method of claim 45 , wherein the at least one additional therapeutic agent comprises one or more agents independently selected from the group consisting of: inhibitors of the CD47-SIRPα pathway (e.g., anti-CD47 antibodies), tyrosine kinase inhibitors , inhibitors of HIF (eg, HIF-2α inhibitors), inhibitors of PARP, RAS signaling inhibitors, immune checkpoint inhibitors, agents targeting extracellular production of adenosine, radiotherapy and chemotherapeutic agents. The method of claim 46 , wherein the at least one additional therapeutic agent comprises an inhibitor of the CD47-SIRPα pathway, wherein the inhibitor of the CD47-SIRPα pathway is an anti-CD47 antibody. The method of claim 46 or 47 , wherein the at least one additional therapeutic agent comprises one or more tyrosine kinase inhibitors that inhibit one or more of: EGFR, VEGFR, HER-2, HER-3, BRAF, PDGFR, MET, MEK, ERK, ALK, RET, KIT, IGFR, TRK and/or FGFR. The method of any one of claims 46 to 48 , wherein the at least one additional therapeutic agent comprises one or more immune checkpoint inhibitors that block the activity of at least one of: PD-1, PD-L1, BTLA , LAG-3, B7 family members, TIM-3, TIGIT or CTLA-4. The method of claim 49 , wherein the one or more immune checkpoint inhibitors comprise an immune checkpoint inhibitor that blocks the activity of PD-1 or PD-L1. The method of claim 50 , wherein the immune checkpoint inhibitor blocking the activity of PD-1 or PD-L1 is selected from the group consisting of: avelumab, atezolizumab ), balstilimab, budigalimab, camrelizumab, cosibelimab, dostarlimab, durvalumab Anti-durvalumab, emiplimab, envafolimab, ezabenlimab, nivolumab, pembrolizumab, pidilizumab, pimivalimab, retifanlimab, sasanlimab, spartalizumab, sintilimab (sintilmab), tislelizumab (tislelizumab), toripalimab (toripalimab) and zimberelimab (zimberelimab). The method of claim 50 , wherein the immune checkpoint inhibitor blocking the activity of PD-1 or PD-L1 is cepalizumab. The method of any one of claims 46 to 52 , wherein the one or more immune checkpoint inhibitors comprise an immune checkpoint inhibitor that blocks the activity of TIGIT. The method of claim 53 , wherein the immune checkpoint inhibitor that blocks the activity of TIGIT is selected from the group consisting of AB308, domvanalimab, etigilimab, and ociperlimab. , tiragolumab or vibostolimab. The method of claim 53 , wherein the immune checkpoint inhibitor is dofenumab or AB308. The method of any one of claims 46 to 55 , wherein the at least one additional therapeutic agent comprises one or more agents targeting extracellular production of adenosine selected from the group consisting of: A _2a R/A _2b R Antagonists, CD73 inhibitors and CD39 inhibitors. The method of claim 56 , wherein the one or more extracellularly produced agents targeting adenosine are selected from the group consisting of: AB598, etrumadenant, inupadenant, tamina Taminadenant, caffeine citrate, imaradenant, ciforadenant and quemliclustat. The method of claim 56 , wherein the one or more extracellularly produced agents targeting adenosine are AB598, elumelon, and/or quinlistat. The method of any one of claims 46 to 58 , wherein the at least one additional therapeutic agent comprises an inhibitor of HIF-2α selected from the group consisting of: bezutifan, ARO-HIF2, PT-2385 and AB521. The method of claim 59 , wherein the inhibitor of HIF-2α is AB521. The method of any one of claims 46 to 60 , wherein the at least one additional therapeutic agent comprises an inhibitor of PARP selected from the group consisting of: olaparib, rucaparib and nil. niraparib. The method of any one of claims 46 to 61 , wherein the at least one additional therapeutic agent comprises a chemotherapeutic agent. The method of any one of claims 46 to 62 , wherein the at least one additional therapeutic agent comprises radiation therapy. The method of any one of claims 46 to 63 , wherein the compound and the at least one additional therapeutic agent are administered in combination. The method of any one of claims 46 to 64 , wherein the compound and the at least one additional therapeutic agent are administered sequentially. The method of any one of claims 46 to 64 , wherein the treatment periods for administering the compound and the at least one additional therapeutic agent overlap. A combination comprising a compound as claimed in any one of claims 1 to 31 , or a pharmaceutically acceptable salt thereof, and at least one additional therapeutic agent. The combination of claim 67 , wherein the at least one additional therapeutic agent comprises one or more agents independently selected from the group consisting of: inhibitors of the CD47-SIRPα pathway (e.g., anti-CD47 antibodies), tyrosine kinase inhibitors , inhibitors of HIF (eg, HIF-2α inhibitors), inhibitors of PARP, RAS signaling inhibitors, immune checkpoint inhibitors, agents targeting extracellular production of adenosine, radiotherapy and chemotherapeutic agents. The combination of claim 68 , wherein the at least one additional therapeutic agent comprises an inhibitor of the CD47-SIRPα pathway, wherein the inhibitor of the CD47-SIRPα pathway is an anti-CD47 antibody. The combination of claim 68 or 69 , wherein the at least one additional therapeutic agent comprises one or more tyrosine kinase inhibitors that inhibit one or more of: EGFR, VEGFR, HER-2, HER-3, BRAF, PDGFR, MET, MEK, ERK, ALK, RET, KIT, IGFR, TRK and/or FGFR. The combination of any one of claims 68 to 70 , wherein the at least one additional therapeutic agent comprises one or more immune checkpoint inhibitors that block the activity of at least one of: PD-1, PD-L1, BTLA , LAG-3, B7 family members, TIM-3, TIGIT or CTLA-4. The combination of claim 71 , wherein the one or more immune checkpoint inhibitors comprise an immune checkpoint inhibitor that blocks the activity of PD-1 or PD-L1. Such as the combination of claim 72 , wherein the immune checkpoint inhibitor blocking the activity of PD-1 or PD-L1 is selected from the group consisting of: avelumab, atezolizumab, batizumab Antibodies, buglimumab, camrelizumab, coscilimab, dotalizumab, durvalumab, ipilimumab, envolizumab, ebenezumab, naphtha Vulumab, pembrolizumab, pitilizumab, pimivumab, refulimab, sarsanizumab, spartalizumab, sintilimab, tisleliz cizumab, toripalimab and cepalizumab. The combination of claim 73 , wherein the immune checkpoint inhibitor blocking the activity of PD-1 or PD-L1 is cepalizumab. The combination of any one of claims 68 to 74 , wherein the one or more immune checkpoint inhibitors comprise an immune checkpoint inhibitor that blocks the activity of TIGIT. Such as the combination of claim 75 , wherein the immune checkpoint inhibitor blocking the activity of TIGIT is AB308, dofenumab, eltilizumab, ospelizumab, tisrelumab or vibrizumab monoclonal antibodies. The combination of claim 76 , wherein the immune checkpoint inhibitor blocking the activity of TIGIT is AB308 or dofenumab. The combination of any one of claims 68 to 77 , wherein the at least one additional therapeutic agent comprises one or more extracellularly produced agents targeting adenosine selected from the group consisting of: A _2a R/A _2b R Antagonists, CD73 inhibitors and CD39 inhibitors. The combination of claim 78 , wherein the one or more extracellularly produced agents targeting adenosine are selected from the group consisting of: AB598, elumelon, elupaline, taminaline, caffeine citrate , Emmarenol, Severilan or Quinlistat. The combination of claim 79 , wherein the one or more extracellularly produced agents targeting adenosine are elumelon and/or quinlistat. The combination of any one of claims 68 to 80 , wherein the at least one additional therapeutic agent comprises an inhibitor of HIF-2α selected from the group consisting of bezutifan, ARO-HIF2, PT-2385 and AB521. The combination of claim 81 , wherein the inhibitor of HIF-2α is AB521. The combination of any one of claims 68 to 82 , wherein the at least one additional therapeutic agent comprises an inhibitor of PARP selected from the group consisting of: olaparib, rucapanib and niraparib. The combination of any one of claims 68 to 83 , wherein the at least one additional therapeutic agent comprises a chemotherapeutic agent. The combination of claim 84 , wherein the chemotherapeutic agent comprises gemcitabine, cytarabine, platinum-based, paclitaxel-based or anthracycline-based chemotherapeutic agent. Such as the combination of claim 85 , wherein the chemotherapeutic agent is selected from the group consisting of: cisplatin, carboplatin, oxaliplatin, doxorubicin, docetaxel docetaxel and paclitaxel. The combination of any one of claims 68 to 86 , wherein the at least one additional therapeutic agent comprises radiation therapy.